Zuschüsse & Fördermöglichkeiten

2026 Early Career Scholars:

Samuel Carrell, MD, PhD 
Assistant Professor of Neurology 
Virginia Commonwealth University, United States

Individuals with DM1 show variable symptoms affecting muscles, heart, and cognition, with age of onset and severity poorly predicted by repeat length alone. This variability complicates clinical care and trial design. The project “Identifying Genetic Modifiers of Disease Severity in Myotonic Dystrophy” aims to identify genetic modifiers that influence disease manifestations by systematically knocking out genes in patient-derived muscle progenitor cells and measuring changes in disease activity. Genes identified will be validated individually in DM1 and control cells. These studies will reveal factors that exacerbate or protect against DM1 symptoms, providing targets for future research and potential therapeutic development.

Katarzyna Taylor, PhD 
Assistant Professor 
Adam Mickiewicz University, Poznan, Poland

DM1 is a genetic disorder affecting multiple organs with no current treatment to slow progression. Many symptoms arise from reduced levels of MBNL1 and MBNL2 proteins, which are essential for normal cellular function. Restoring MBNL levels offers therapeutic potential, but precise control is critical to avoid harmful effects. This research project “Mechanisms of MBNL Regulation: Molecular Targets for Potential Therapeutic Intervention in DM1” aims to identify regulatory mechanisms controlling MBNL1 and MBNL2 expression, providing new targets for therapy. Understanding these mechanisms could enable fine-tuned treatments, alone or in combination, and accelerate development of personalized interventions tailored to disease stage, progression, and individual patient needs.

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2026 High-Priority Grants:

Curtis Nutter, PhD
Assistant Professor 
University of Missouri, Columbia, MO, United States

DM1 affects multiple organs, with brain symptoms such as fatigue, cognitive difficulties, and low motivation severely impacting daily life. Current methods cannot reliably measure these symptoms or treatment effects. This project focuses on the choroid plexus, which produces cerebrospinal fluid (CSF), and its abnormal RNA splicing in DM1. The study “Choroid plexus RNA Mis-splicing Drives Cerebrospinal Fluid Biomarker Changes in DM1” will analyze brain and CSF samples from patients and use lab-grown brain tissues to test treatments. The goal is to identify CSF biomarkers that reflect brain dysfunction, enabling better disease monitoring, evaluation of therapies, and development of new brain-targeted treatments to improve quality of life for people with DM1.

2025 Early Career Scholars:

Lukasz Jakub Sznajder, Ph.D.  
Assistant Professor
University of Nevada, Las Vegas, NV, US 

DM2 has been significantly less studied than DM1, with no approved treatments or clinical trials available. Developing tailored therapeutic approaches based on the specific molecular mechanisms of DM2 is crucial. While both DM types share some molecular features, DM2’s mechanism is more complex. Evidence suggests that DM2 results primarily from the toxicity of expanded CCUG RNA repeats, but the exact form of the toxic RNA remains unclear. Previous studies have shown that these repeats are retained in aberrantly spliced mRNA, which is exported to the cytoplasm—a crucial discovery in understanding DM2. This project “Probing Expanded RNA Species and Their Role in DM2” aims to test whether mRNA with retained CCUG repeats is a key pathogenic molecule in DM2 and to develop therapeutic strategies to prevent such retention. Furthermore, a cost-effective method will be created to detect and quantify intron retention. Using DM2 cell lines and tissues, along with bioinformatics and molecular biology tools, this project will provide insights into the DM2 mechanism and lay the groundwork for future therapeutic development. Click here to read more about Dr. Lukasz Jakub Sznajder.

Scott Uhlrich, Ph.D.  
Assistant Professor, Director of Movement Bioengineering Laboratory 
The University of Utah, Salt Lake City, UT, US 

While new drugs are in development for DM1, clinical trials are limited by inadequate outcome measures for evaluating effectiveness. Existing measures, such as the 10-meter walk test, are not sensitive to subtle changes in movement quality or the many aspects of daily function that impact quality of life. This project “Novel digital functional outcome measures for myotonic dystrophy using smartphone video” aims to develop a digital functional outcome measure using OpenCap, a software that measures human motion with two smartphone cameras. The project has two goals: 1) create a video-based measure that captures multiple activities affected by DM1, using machine learning to assess deviations in movement; and 2) test the feasibility of home-based assessments with a single smartphone camera. By measuring daily function remotely, this new approach could improve sensitivity, reliability, and accelerate clinical trials for DM1 treatments. Click here to read more about Dr. Scott Uhlrich.

2025 High-Priority Grants:

Katarzyna Taylor, Ph.D.  
Research Assistant Professor
Adam Mickiewicz University (Uniwersytet im. Adama Mickiewicza w Poznaniu), Poznan, Poland

MBNL plays a crucial role in promoting alternative splicing patterns and maintaining cell differentiation. In DM1, the depletion of the MBNL pool impairs cellular function. Current research focuses on strategies to replenish functional MBNL levels, as uncontrolled overexpression can lead to negative consequences. Understanding and regulating the endogenous expression of MBNL is essential, as mild increases in MBNL concentration can avoid adverse effects. Fine-tuning MBNL levels may provide novel therapeutic opportunities, potentially in combination with other treatments. A molecule targeting MBNL expression is currently undergoing clinical trials. However, the mechanisms regulating MBNL expression remain largely unexplored. The project “Identification of novel molecular mechanisms of MBNL1 expression as potential DM therapeutic targets” aims to identify novel regulatory elements controlling MBNL1 expression, expanding therapeutic targets and contributing to the development of personalized or combination therapies based on disease onset, progression, and individual patient response.

Samuel Carrell, M.D., Ph.D.  
Assistant Professor of Neurology
Virginia Commonwealth University, Richmond, VA, US 

Individuals with myotonic dystrophy exhibit common symptoms such as muscle weakness, cramping, heart rhythm issues, and cognitive difficulties. However, the age of onset, severity, and specific symptoms vary widely among patients. The disease is caused by an expansion in a gene’s repetitive sequence, which correlates with the timing of symptom, though only about 20% of the variability is explained. This uncertainty complicates clinical trial planning and medical care. Given this variability, the project “Identifying Genetic Sources of Disease Variability in Myotonic Dystrophy Type 1” hypothesizes that additional genetic factors contribute to or protect against disease manifestations. To identify these genes, Dr. Carrell plans to systematically knock out each gene in muscle progenitor cells derived from patients with DM1 and DM2. By measuring activity, he will sort the cells based on their response and validate the genes that influence disease progression, paving the way for future research to understand their impact on DM patients.

2025 Pilot Grants:

Kate Eichinger, PhD 
Physical Therapist 
University of Rochester, New York, US 

Currently, there are no FDA-approved treatments for DM1, though promising clinical trials are underway. One challenge with clinical trials is identifying ways to detect changes in function, as traditional tests show small differences over time. New technology, like wearable sensors, offer a potential solution. These sensors collect data while a person performs walking and balance tasks. Data is then processed to provide objective and precise measures of function. Wearable sensors and the derived measures have been used successfully in other conditions and have shown potential to detect early changes in function. The study “Wearable Sensors to Monitor Gait and Balance in Individuals with Myotonic Dystrophy” will use wearable sensors to collect data on walking and balance in adults with DM1. By analyzing this data, the researchers aim to identify reliable and accurate methods to detect changes in function earlier. These new methods could help health care providers and researchers better understand how DM1 affects walking and balance, leading to more effective care and paving the way for improved health, wellness, and quality of life in individuals with DM1. Click here to read more about Dr. Kate Eichinger.

Juan Manuel Fernandez, PhD 
Senior Researcher 
Fundacio Institut de Bioenginyeria de Catalunya (Institute for Bioengineering of Catalonia), Spain 

DM2 is caused by a specific genetic mutation that disrupts the normal function of cells, leading to widespread effects on muscle and other tissues. Despite its impact, there are no effective treatments for DM2, partly because there is a lack of reliable models to study the disease and test new drugs. The Biomimetic Muscle Models for in vitro functional analysis and drug assessment in DM2 (BMM-2) project aims to tackle this challenge by creating a groundbreaking „muscle-on-a-chip“ platform. This platform uses 3D muscle tissues grown from cells donated by DM2 patients. These tiny muscle tissues are engineered to behave like real muscles, even showing features of DM2 such as weakness and myotonia. To make these tissues as lifelike as possible, they grow them on special materials that mimic the structure of muscle and use electrical stimulation to improve their development and function. This approach allows them to measure how the disease affects muscle strength and movement. In addition, they will analyze the fluid surrounding the muscle tissues to find molecules, called biomarkers, that could help us track the disease or measure how well new treatments are working. These biomarkers will eventually be used in tiny sensors integrated into the platform, providing real-time feedback during drug testing. This project has the potential to transform the study of DM2 and develop new therapies. By combining advanced engineering, patient-derived cells, and biosensor technology, they aim to create a cost-effective tool that allows for faster and more accurate drug testing. In the future, this platform could also help doctors personalize treatments for patients and monitor their progress over time. Click here to read more about Dr. Juan Manuel Fernandez.

David Housman, PhD and Christopher Ng, Sc.D.  
Ludwig Professor of Biology/ Research Scientist 
Massachusetts Institute of Technology – MIT, Cambridge, Massachusetts, US 

The project “A Targeted DNA Repair Enzyme Therapy for Myotonic Dystrophy” aims to develop a groundbreaking therapy that uses a specialized viral system, called an adeno-associated virus (AAV), to deliver a therapeutic protein directly into muscle cells. This protein, which is part of the body’s natural DNA repair machinery, has the ability to stabilize the disease-causing CTG repeat expansions and prevent them from worsening over time. By reducing further damage to the DNA, this approach has the potential to protect muscle cells, improve their function, and slow the progression of the disease. Unlike current therapies that treat only symptoms, this strategy targets the root cause, offering the potential for a disease modifying treatment.
In the first phase of this research, they will test how effectively the AAV therapy delivers the therapeutic protein to muscle cells, using samples donated by patients with DM1. These experiments will help confirm that the therapy can be delivered efficiently and works as expected to stabilize the CTG repeats. In the second phase, they will test the therapy in a well established mouse model of DM1. They will evaluate its ability to stabilize the DNA in skeletal muscle tissues and assess whether it has any side effects to ensure the approach is safe. In the future, they plan to expand these studies to evaluate how the therapy works in other tissues affected by the disease, such as the heart and smooth muscle. They will also work to optimize the therapy for long-term safety and effectiveness, with the ultimate goal of advancing it into clinical trials. Click here to read more about Dr. David Housman and Dr. Christopher Ng.

Stephanie Tome, PhD 
Research Associate
Sorbonne Université-Inserm UMRS974, Paris, France 

Unfortunately, current methods for analyzing the genetic repeats in DM2 are limited. This makes it difficult to understand the relationship between genetic factors and symptoms, how the disease progresses, and what influences its severity. As a result, DM2 is not well understood, and the lack of clear links between genetic and genomic factors and clinical symptoms and disease progression complicates study design, hypothesis testing, clinical trials, genetic counseling, thereby offering little predictive information about the disease’s course. The goal of the study, “Redefining the Genotype-Phenotype Paradigm in Myotonic Dystrophy type 2”, is to use advanced genome sequencing technologies to better study the repeat region (size and composition) and to understand how genetic factors are linked to symptoms in DM2. By analyzing data from a large group of DM2 patients, the researchers hope to improve diagnosis and prognosis, ultimately leading to better care and support for people living with DM2.

Arianna Tucci, MD, PhD 
Clinician Scientist
Queen Mary University of London, England, UK 

The study, “Myotonic dystrophy type 2: using genomics to understand frequency and expressivity of the disease”, aims to fill critical gaps in understanding DM2. First, by analyzing data from large population studies like the UK Biobank (500,000+ individuals), researchers will determine the frequency of the genetic mutation that causes DM2 across diverse groups. This analysis may also identify milder, misdiagnosed cases, including those classified as fibromyalgia, and reveal the true prevalence of DM2. Second, advanced techniques like long-read DNA sequencing will provide a detailed examination of DM2-related genetic changes, offering insights into disease variability. By integrating cutting-edge technology with large-scale genomic data, this study aims to improve DM2 diagnosis, recognition, and future treatment development.

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2025 Research Fellows:

Louison Daussy, MSc  
Graduate Student 
Institut National de la Santé et de la Recherche Médical – DR Paris Centre Est, Paris, France 

The neurological symptoms of DM1 significantly affect daily life, leading to cognitive challenges, low education levels, unemployment, and social deprivation. Future treatments could improve social integration by enhancing education and employment opportunities, reducing the socioeconomic burden on patients and their families. The effects of DM1 on the brain remain poorly understood. Initial findings reveal that DM1 disrupts neuron morphology and vesicle transport, which are critical for neurotransmitter release and brain communication. This discovery opens new avenues for research. The project “DM1 Neuropathology: From Neuronal Morphology and Axonal Transport to the Reversion of Brain Disease” aims to investigate neuron-specific aspects of DM1 and test strategies to correct them. Using mouse models, the study will examine how DM1 affects neuron morphology, function, and signaling proteins. A novel model will assess whether reversing gene expression in neurons can alleviate brain symptoms. This research will deepen understanding of DM1’s neurological effects, inform targeted therapies, and address the critical question of whether brain symptoms can be reversed. Click here to learn more about Louison Daussy.

Emily Davey, BS
Graduate Research Assistant
University of Florida, Gainesville, FL, US 

DM1 affects the brain, causing symptoms like excessive daytime sleepiness, apathy, and difficulties with learning and memory, which patients report as major burdens. However, little is known about the underlying causes of these symptoms. The brain consists of multiple regions with unique functions, but previous studies have focused only on a few regions in a limited number of patients. This project “Uncovering regional and cell-type specific transcriptomic signatures in the DM1 brain” aims to study global RNA-level changes in 11 brain regions of DM1 patients to identify whether changes are localized or widespread. Since each brain region contains various specialized cell types, the study will use methods that track the RNA of individual cells to determine which types are affected. This approach will also quantify the proportion of affected cells within each type. Ultimately, this research will create a transcriptomic atlas of the DM1 brain, providing insights into the regions and cell types driving the observed symptoms. Click here to learn more about Emily Davey.

Diana Alejandra Madrid Fuentes, MSc 
Doctoral Student
Wake Forest University Health Sciences, Winston-Salem, NC, US 

Effective biomarkers are crucial for understanding diseases, developing treatments, and monitoring treatment response over time. MRI shows promise as a biomarker, as it is non-invasive, widely accessible, and highly accurate, with success in other muscular dystrophies. The study “Validating Muscle MRI as a Biomarker of Disease Status in DM2” aims to fill a gap in DM2 research by collecting lower extremity MRI data from DM2 patients and healthy controls. Using an open-source AI approach, the study will assess muscle characteristics, such as fat percentage and muscle tissue capable of generating force. Specialized muscle images will also be analyzed for edema. The study will validate these MRI measures against motor outcomes like muscle strength and walking speed. Building on ongoing DM2 brain imaging research, this study provides an efficient, cost-effective approach to determine if quantitative MRI is a viable biomarker for DM2. Click here to learn more about Diana Alejandra Madrid Fuentes.

Haneui Bae, PhD
Postdoctoral Research Associate
University of Illinois Urbana-Champaign, Urbana, IL, US 

Clinicians and researchers have so far focused on the symptoms in skeletal muscles, heart, and brain; however, many DM1 patients also suffer from metabolic and liver-specific symptoms, such as metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic syndrome. In addition, patients also experience heightened sensitivity to a wide range of anesthesia, muscle relaxants and other drugs, resulting in prolonged recovery time, respiratory depression, increased risk of complications during surgical procedures, and broadly altered drug metabolism. These manifestations indicate malfunctioning of the liver, a major site of nutrient and drug metabolism, yet this possibility has not been investigated thoroughly. The project “Investigating the molecular mechanisms of liver dysfunctions in myotonic dystrophy” aims to understand the precise mechanisms of DM1 pathogenesis in the liver and identify targets for therapeutic intervention. Understanding how nutrient and drug metabolism is disrupted in DM1 will have important translational implications for developing new therapeutics and managing the health and lifestyle of DM1 patients. Click here to learn more about Dr. Bae.

Cécilia Légaré, PhD 
Postdoctoral fellow
Research Foundation of SUNY – University at Albany, NY, US 

DM1 patients experience symptoms like muscle weakness, difficulty relaxing muscles, and respiratory problems. While there is no cure, treatment focuses on managing symptoms. Recently, strength-training programs have shown promise as a therapeutic approach. Dr. Légaré’s team developed a 12-week program to address muscle weakness in DM1 patients. Their results showed improvements in lower body strength, walking speed, and daily function in men, with similar gains in women. However, the molecular mechanisms behind these improvements are not yet understood. Building on findings from male patients, in the project “Identification of a transcriptomic signature in myotonic dystrophy type 1” the team will now study female DM1 patients to compare molecular responses to training. They will also examine molecular changes over three years to assess long-term effects. Additionally, the team will explore non-invasive biomarkers by analyzing saliva samples from DM1 patients and healthy individuals, aiming to develop more effective, non-invasive disease markers. Click here to learn more about Dr. Légaré.

2024 Pilot Grants:

Joel R. Chamberlain, Ph.D. 
Research Associate Professor
University of Washington, Seattle, WA, US

Project: Efficacy Testing of Cell-Derived Nanovesicle Delivery of Small Interfering RNAs for Treatment of DM1

Dr. Chamberlain is exploring a novel approach to treat DM1 by using natural cell-derived vesicles to deliver drugs that can destroy toxic RNA structures in muscles. If successful, this could lead to a new, non-invasive treatment that targets the root cause of DM1. Click here to learn more about Dr. Chamberlain.

Paloma Gonzalez Perez, M.D., Ph.D.  
Neuromuscular Attending
Massachusetts General Hospital, Boston, MA, US

Project: Investigating Benefits of a Physical Therapist-Guided Exercise Program in Myotonic Dystrophy Type 2

Dr. Gonzalez Perez is testing the effectiveness of a simple, guided exercise program designed to improve motor function and reduce pain in DM2 patients. Her study will examine the long-term benefits of exercise under physical therapist supervision, with the goal of making this program accessible to more DM2 patients. Click here to learn more about Dr. Perez.

Emma Matthews, FRCP  
Reader of Neurology and Consultant Neurologist 
St George’s, University of London, UK

Project: Exploring Transcriptional Dysregulation of Lipid Metabolism Genes in DM1

Dr. Matthews aims to uncover why DM1 patients are more prone to abnormal lipid profiles (dyslipidemia). By comparing lipid metabolism genes in DM1 patients with and without dyslipidemia, her study could lead to better treatment guidelines and new therapies for managing this condition. Click here to learn more about Dr. Matthews.

Belinda Pinto, Ph.D.  
Research Assistant Scientist
University of Florida, Gainesville, FL, US

Project: Investigating the Contribution of Circadian Disruption to Hypersomnolence in Myotonic Dystrophy

Dr. Pinto is studying how disruptions in the circadian system contribute to excessive daytime sleepiness in DM1 patients. Using animal models, she seeks to understand the molecular causes of hypersomnia and pave the way for future therapeutic developments. Click here to learn more about Dr. Pinto.

2024 Early Career Scholars:

Johanna Hamel, MD
Assistant Professor
University of Rochester, New York, US

DM1 exhibits considerable variability, even within families. Symptoms can emerge at any life stage, with earlier onset often indicating a more severe form. The underlying CTG repeat mutation, measured in blood cells, ranges widely from >50 to >1000 repeats. Initially, it was believed that this repeat length reliably predicted symptom timing and severity, but recent research challenges this, sparking ongoing debate in the medical community. This uncertainty complicates the work of healthcare professionals managing diverse symptoms and genetic factors, especially in clinical trials for new treatments. Dr. Hamel’s pilot study demonstrated the feasibility of remote assessments for DM1 via video conferencing and toolkits. Her larger study “Remote Assessments in Myotonic Dystrophy” aims to assess the role of repeat length in disease onset and severity, reaching individuals across the country, including those underrepresented in research. This proposal aims to expand the remote research platform, enhance community involvement, and lay the groundwork for Genome-wide Association Studies. By exploring residual variance in symptom onset not explained by repeat length, the study aims to identify genetic modifiers. Integrating genetic and clinical data into patient registries improves them as valuable research tools, streamlining patient recruitment and categorization for future therapeutic trials, ultimately enhancing trial effectiveness and reducing patient burden. Click here to read more about Dr. Johanna Hamel.

Tahereh Kamali, PhD
Postdoctoral Research Fellow
Stanford University School of Medicine, California, USA

DM affects various organ systems, including the Central Nervous System (CNS). Despite being a primary concern for patients, understanding CNS symptoms remains limited due to the complex nature of CNS function and a lack of clinical data. The scarcity of complete clinical data poses a significant challenge in DM research, hindering robust statistical analyses and the effectiveness of clinical trials. This limitation makes it challenging to identify reliable biomarkers and validate outcome measures for targeted therapies. Despite efforts to share data between healthcare institutions, the rarity of DM restricts the number of patients available for study, impeding advancements in researchers‘ understanding and treatment development. In recent years, Dr. Tarareh Kamali’s team made strides by creating an artificial intelligence (AI) model capable of identifying specific CNS changes indicative of DM progression. Their next step involves enhancing this AI model, addressing data scarcity by creating synthetic yet realistic CNS data and incorporating real-world patient data. This innovative project “Utilizing Generative AI to Expand Clinical Data for DM Studies and Treatment Efficacy Planning” aims to revolutionize DM research, facilitating more accurate diagnoses and personalized treatments. By deepening our understanding of how DM affects the CNS, the research seeks transformative strategies that can alter the disease’s course, offering hope and improved quality of life for those affected. Leveraging cutting-edge technology, this project brings us closer to unraveling the complexities of DM, paving the way for effective treatment strategies and a healthier future for individuals with this condition. Click here to read more about Dr. Tahereh Kamali.

2024 High-Priority Grants:

These grants are for $50,000, over one year, for Early Career applications designated as high priority by the MDF Board. The funding provides interim research support designed to enable the Principal Investigator to gather additional data.

Kristina Kelly, DPT
Assistant Research Professor
University of Missouri-Columbia, Missouri, US

Fatigue poses a significant yet underexplored challenge for individuals with DM1. Understanding the underlying biology of fatigue is crucial for developing effective interventions. One facet of fatigue is motor fatigability, characterized by a measurable decline in physical performance during a specific task. To investigate, they will examine the nervous system’s role, a component often influenced by DM1. The study “Neural Mechanisms of Motor Fatigability in Myotonic Dystrophy Type 1” involves individuals with DM1 and healthy controls, evaluating motor fatigability using clinical measures. In the first phase, we will analyze nervous system activity in the quadriceps muscles, comparing those with DM1 experiencing motor fatigability, those without, and healthy controls. Anticipated findings include reduced nervous system activity in those with motor fatigability. The second phase assesses nervous system activity post-30 minutes of cycling exercise, aiming to understand differences among participants. They hypothesize distinctive responses in the nervous systems of those with DM1 and motor fatigability. While exercise benefits individuals with DM1, understanding its impact on fatigue is essential for personalized recommendations. Cycling, a safe and feasible exercise, was chosen to broaden the study’s applicability. By investigating real-world movements resembling those causing fatigability, they aim to provide insights applicable to a wider DM1 population. This study marks a crucial initial exploration into DM1 fatigue biology, laying the groundwork for future interventions to enhance the lives of individuals with DM1. Click here to learn more about Kristina Kelly.

Lukasz Sznajder, PhD, MSc
Assistant Research Professor
University of Nevada, Las Vegas, US

DM2 has garnered less attention than DM1, lacking approved treatments or clinical trials. The uncertainty persists in applying DM1 therapeutic strategies to DM2. Tailoring approaches to the DM2 molecular mechanism is crucial. Despite commonalities, DM2’s mechanism seems more intricate. Evidence points to expanded CCUG RNA repeats‘ toxicity as the primary cause. The prior research unveiled that these repeats persist in an improperly spliced mRNA exported to the cytoplasm, a vital revelation. Yet, confirmation that this mRNA constitutes a pathogenic molecule in DM2 is pending. This project “Delineating pathogenic RNA species in myotonic dystrophy type 2” aims to validate the hypothesis that mRNA with retained CCUG repeats is a key pathogenic factor in DM2, driving characteristic molecular changes. Additionally, they will develop preventative therapeutic strategies. Leveraging DM2-derived cell lines, and tissues, and employing bioinformatics and molecular biology tools will help achieve these objectives. Identifying primary pathogenic molecules will enhance the understanding of DM2 and lay the groundwork for therapeutic development. Click here to learn more about Dr. Sznajder.

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2024 Research Fellows:

Betty Bekele 
Emory University, Atlanta, Georgia, US

In people with Myotonic Dystrophy Type 1 (DM1), one of the most common non-muscle symptoms is disordered sleep such as trouble falling asleep at night, sleeping for extended hours during the day, and sleep apnea (obstruction of breathing during sleep). Moreover, DM1 patients face unique challenges related to anesthesia including increased sensitivity to drugs, delayed recovery, and respiratory complications that can be fatal. This study “Altered Inhibitory Neurotransmission in Mouse Models of Myotonic Dystrophy Type 1 (DM1)” delves into the impact of DM1 on Gamma-Aminobutyric Acid (GABA), a crucial brain chemical for sleep and anesthesia sedation. GABA controls how active or “excited” our brain cells (neurons) are through special channels called GABAA receptors that are found on the surface of neurons. These channels have different parts called subunits which are like puzzle pieces. The combination of these subunits can change as we grow up. Moreover, each subunit can have different versions (isoforms) because of a process called „alternative splicing,“ which is like mixing and matching puzzle pieces to create unique proteins that can perform different functions. In the adult brain, most GABAA receptors are made up of three parts: alpha1, beta1, and gamma2. The gamma2 subunit is essential for the function of most anesthetic drugs and has two splice variants: a longer one called „gamma2L“ and a shorter one called „gamma2S.“ The longer isoform gamma2L is found at specific neuronal connections (synapses), while the shorter isoform gamma2S is found in places outside of the synapse (extrasynaptic sites). In people with DM1, the short variant gamma2S is found at higher levels than the long variant gamma2L Using mouse models of DM1, the study records neuronal electrical activity to understand how this isoform shift influences GABA and GABAA receptor-targeting drugs. By examining how drugs affect neuronal activity, they will gain insights into DM1’s impact on the brain and can test potential therapies. One such drug under consideration is flumazenil, aimed at reversing GABA’s effects to alleviate sleep issues and counter anesthesia effects. This approach not only enhances the understanding of DM1’s neurological aspects but also offers a pathway for testing promising treatments to improve patient outcomes. Click here to read more about Ms. Betty Bekele.

Sakura Hamazaki
University of Rochester, New York, US

DM1 affects various organs, presenting symptoms like myotonia, weakness, and muscle wasting. Despite being one of the most debilitating aspects of DM1, the direct cause of muscle weakness and wasting is yet to be understood. This has been particularly challenging due to the widespread effect of the genetic lesion responsible for DM1; however, without the understanding of these specific targets, generating therapeutics for patients is difficult. Recent research points to altered ion channels crucial for muscle contraction as contributors to DM1-related weakness. To explore this further, they have developed mouse models expressing these channels, pinpointing one that, when forced into DM1-like conditions, leads to reduced lifespan and muscle/respiratory issues. This discovery establishes a potential therapeutic target. The next step involves correcting this channel’s function, assessing its impact on overall muscle health using established mouse models to validate therapeutic benefits. Unlike conventional drug testing, this method minimizes concerns about unintended effects. Successfully completing this study “Impact of calcium entry through Cav1.1 in myotonic dystrophy myopathy” will definitively identify ion channels as new therapeutic targets for DM1 myopathy, bolstering confidence in developing novel treatments or repurposing existing FDA-approved drugs. Click here to read more about Ms. Sakura Hamazaki.

Alexandra L. Marrero Quinones
Virginia Commonwealth University, Richmond, Virginia, US

DM1 results from a DNA repetition (CTG repeat) in the DMPK gene, expanding across generations. In general, CDM children are born to DM1 mothers with high repeat loads who experience disease early in life. However, some children born to mildly affected mothers unexpectedly develop severe symptoms from a rapid repeat expansion. The cause of this rapid expansion is unclear, but it’s suspected to involve genes repairing damaged DNA. To address this question, blood samples from 45 CDM patients and parents were collected. In preliminary work with 10 families with rapid expansion, they found damaging variations in the DNA repair gene MSH3. These variations, inherited with the DM1-causing gene, impair global DNA repair in cells. This suggests a link between MSH3 variants and DM1 repeat instability, contributing to the rapid genetic changes observed with maternal inheritance. In the “Evaluation of MSH3 as a Genetic Modifier of Trinucleotide Repeat Instability in Myotonic Dystrophy” project it is their objective to further evaluate the role in DM1 repeat instability of these MSH3 variants and other inherited DNA repair variants identified through DNA sequencing of families with rapid repeat expansions. This may identify new potential therapeutic targets while providing insight into the role of DNA repair mechanisms in DM1 CTG repeat instability and the progression of disease. Click here to read more about Ms. Alexandra L. Marrero Quinones.

Cameron Niazi
University of Florida, Gainesville, Florida, US

DM1 is a genetic disorder caused by a gene that, when broken, produces a toxic RNA that makes the patients’ cells sick. The faulty gene is like a broken faucet pumping out dirty water (RNA) that contaminates the cell that it empties into. Traditional treatments focus on eliminating or neutralizing the toxic RNA, but the underlying issue persists—the broken gene keeps producing harmful RNA. Advances in CRISPR/Cas gene editing offer a new approach to fix the gene by using „molecular scissors“ to cut and repair the patient’s DNA, effectively fixing the broken faucet. However, safety concerns surround using CRISPR/Cas in humans, as the „molecular scissors“ may inadvertently cut the wrong gene, leading to severe consequences like cancer or other serious adverse events. The project “Leveraging CRISPR/Cas-based Epigenetic Modifications for the Treatment of Myotonic Dystrophy Type 1” represents a modified CRISPR/Cas based “epigenetic silencing” approach that has fewer safety risks compared to most gene editing strategies being pursued for DM1. Epigenetics refers to factors that control how genes are turned on and off. Rather than using “molecular scissors” to go in and cut the problematic DNA. Instead of cutting the problematic DNA, this approach removes CRISPR’s „molecular scissors“ blades, turning the gene off without physically altering it. Using this approach, we can shut off the faucet and stop the toxic RNA from being pumped into the cell without the risks associated with cutting the gene. CRISPR/Cas based targeted epigenetic therapeutics to turn genes “on” and “off” have attracted significant attention and funding in biotech and pharmaceutical industries. However little work has been done to adapt this technology for DM1. The proposed work will be a first step to bringing this promising new technology to the DM1 community and will serve as a valuable test of its overall feasibility as a therapeutic approach. Click here to read more about Mr. Niazi

2023 Early Career Scholars:

Dylan Farnsworth, PhD
Senior Research Scientist
The RNA Institute, University of Albany, New York, US

Myotonic dystrophy (DM) disrupts gene expression across almost all organ systems. Within these organs, there are many distinct cell types formed by the expression of genes that are specific to a cell’s function. For example, muscle, bone, and intestinal cells all express a different set of genes, which will all be affected differently by the DM repeat expansion. In order to understand how the DM mutations cause symptoms, researchers must first understand which cells express the genes that lead to DM, and second, how the expression of all genes required by these cells is affected in DM. One of the best ways to address this issue is using zebrafish, a vertebrate model organism with recreated genetic mutants that cause DM in humans. This can simultaneously allow researchers to analyze the gene expression patterns of many cell-types across the entire animal. In the project, “Connecting cell-type specific gene-expression patterns in DM-model zebrafish to sleep and circadian disruptions and enhanced therapeutic development”, Dr. Farnsworth and colleagues will link DM-causing genes with cell-types, and cell-types with symptoms. They will use this knowledge to test drugs on zebrafish that can rescue these cell-type specific gene expression patterns and alleviate DM symptoms. Specifically, zebrafish with DM-associated mutations have defects in gastrointestinal (GI) function and regulation of circadian genes that mirror the digestive symptoms and sleep disruption reported by DM patients. Since drug-testing in zebrafish is very rapid and accessible, they will test currently available drugs for their ability to alleviate these DM symptoms. Click here to read more about Dr. Dylan Farnsworth.

Matteo Garibaldi, MD, PhD
Assistant Professor
Sapienza University of Rome, Italy

Muscle weakness in myotonic dystrophy type 1 (DM1) is the consequence of progressive fat replacement of muscles. Muscle MRI studies can reveal if muscles are spared or affected. In many muscle diseases fat replacement is preceded by hyperintense signal in specific MRI sequences (STIR), representing a signature of disease ‘activity’. Consequently, muscle MRI can reveal unaffected muscles, actively affected but still unreplaced muscles, and affected muscles. Some muscles in DM1 are early affected while others remain spared in the course of the disease. This phenomenon leads to a disease-specific pattern of muscle involvement detectable by muscle MRI. Dr. Garibaldi and colleagues recently reported muscle MRI data from a large cohort of DM1 patients showing that DM1 muscle involvement is characterized by progressive fat replacement that is preceded by a period of STIR positivity. In the project, “TranSTIRomics for DM1 – Where the disease begins: a muscle MRI-based transcriptome study in myotonic dystrophy type 1”, Dr. Garibaldi and colleagues aim to understand the biological processes occurring in STIR+ muscles by histopathological and transcriptome (gene expression) analyses. This study will reveal novel insights into pathophysiological mechanisms of muscle weakness in DM1. This will allow a better understanding of what happens when the disease begins and provide novel biomarkers and potential therapeutical targets for the earliest stages of disease. The results will be important for timing the start of treatments, allowing for the identification and treatment of patients in the earliest stages of disease, when the disease switches from a quiescence state to the active-pre-symptomatic phase, anticipating fat replacement and preventing muscle weakness. Click here to ready more about Dr. Matteo Garibaldi.

Melissa Hale, PhD
Assistant Professor
Virginia Commonwealth University, Richmond, Virginia, US

Children with congenital myotonic dystrophy (CDM) present with a unique set of symptoms compared to adults with myotonic dystrophy type 1 (DM1). Unlike in adults, where muscle symptoms decline with age, CDM muscle symptoms often improve in early childhood. How this change occurs is unknown. To date, most research on this has been defined in the context of adult-onset DM1. However, with the distinct presentation of CDM, it is Dr. Hale’s expectation that other cellular processes may occur in CDM children. To address this hypothesis, she recently performed large-scale RNA sequencing to discover differences in the muscle of CDM children across childhood development using muscle biopsies from 34 CDM individuals from 2 weeks – 16 years of age. To date, this is largest dataset of its kind focused exclusively on CDM. This analysis revealed that markers of muscle cell dysfunction in CDM universally improve in early childhood, often to the level of unaffected children, post-severe disease onset at birth. This matches the period where muscle function improves in patients. The goal of her project, “Defining contribution of muscle stem cell activation to dynamic congenital myotonic dystrophy transcriptome”, is to investigate the contribution of a unique population of cells in skeletal muscle, called muscle stem cells (MuSCs), to the molecular signatures observed. MuSCs represent a unique population of cells embedded in all muscles of the body that can regenerate and repair muscle. An understanding of their activity in CDM across childhood development will not only provide a better understanding of the disease but may illuminate potential new therapeutic targets for the most severely affected patients. Click here to read more about Dr. Melissa Hale.

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2023 Research Fellows:

Mackenzie Davenport, PhD
University of Florida, Gainesville, Florida, US

In recent years, it has been shown that the African spiny mouse Acomys cahirinus has remarkable regenerative capabilities, including the ability to repeatedly regenerate its muscle perfectly following repetitive cardiotoxin-induced injury. This is the first mammal ever shown to regenerate following such injuries, and thus opens nearly countless new avenues of study for mammalian regeneration and the translation of such improved regeneration to other mammalian species, including humans. The goal of Dr. Davenport’s study, “Regenerative failure in myotonic dystrophy: pathomechanisms and insights from a novel model of improved regeneration”, is to investigate the role of muscle regenerative failure in contributing to muscle wasting in myotonic dystrophy (DM) and translate their pro-regenerative findings from spiny mice to traditional DM mouse models. Here, Dr. Davenport and colleagues plan to identify pro-regenerative genes from their spiny mouse injury model that modulate regeneration and subsequently test the ability of these genes to promote rapid muscle regeneration and prevent muscle wasting in mouse DM1 and DM2 models as a prelude to developing therapeutic strategies to treat the advanced stages of these diseases. Click here to read more about Dr. Davenport and her work.

Julie Fortin, PhD
Groupe de recherche interdisciplinaire sur les maladies neuromusculaires (GRIMN), Jonquière, Québec, Canada

Fatigue, daytime sleepiness, and apathy are common symptoms that have debilitating effects for individuals with myotonic dystrophy type 1 (DM1) their family. Due to their tremendous impacts, these symptoms are considered some of the next important targets for drug development. Sleepiness and fatigue are commonly used terms in the general population, but their significance can be expressed differently according to different medical conditions. Apathy, defined as a reduction in the initiation of self-directed behaviors, is more frequent in DM1 than in the general population. However, the specific character of the underlying subjective experience of these three symptoms is needed in DM1. Having a patient-reported outcome for each symptom is essential to support healthcare professionals and clinical trial readiness as previous outcome measures have shown to be problematic in DM1- namely because they do not represent the experience of patients. The project, “Development of patient reported outcome measures for CNS manifestations”, will aim to 1) define in detail fatigue, sleepiness, and apathy concepts based on the experience of persons living with DM1 and 2) develop questionnaire that will assess these three concepts. The results of the present project could have major impacts on both the ability to conduct therapeutic trials on (central nervous system) CNS-related symptoms and patients’ care with better evaluation of chronic CNS-related symptoms. Click here to learn more about Dr. Fortin and her work.

Tatiana Koike, PhD
Université de Montreal, Quebec, Canada

There is a strong therapeutic potential to develop strategies targeting defective muscle stem cells for the treatment of myotonic dystrophy type 1 (DM1). However, this avenue remains unexplored. The main goal of Dr. Koike’s project, “Targeting defective muscle stem cells in DM1”, is to target the defective muscle stem cells as a new therapeutic avenue for the treatment in DM1. Dr. Koike and her colleagues hypothesize that drugs that can specifically eliminate these defective cells, which will restore the regenerative capacity of the muscle stem cells and enhance muscle growth and function. They will first determine the efficacy of these drugs in vitro using cells collected from muscle biopsies of patients diagnosed with DM1 to identify the most promising molecules. Thereafter, these lead molecules will be validated in vivo using preclinical animal models and clinically relevant outcomes. This translationally-oriented preclinical project has a high potential to move into clinical trial, especially because they will focus on drugs that are already approved by the FDA or currently used in clinical trials for other diseases. This drug repurposing ensures that these drugs are already safe and effective, which would speed up the translation toward clinical trials. Moreover, since these drugs target a completely novel mechanism of the disease, it could be highly complementary to other therapies currently under investigation, which could maximize the beneficial impact for the patients. Overall, this project will provide a better comprehension of the mechanism contributing to the progression of the disease and it will set the foundation of a new therapy to improve the quality of life of patients that currently have very limited therapeutic options. Click here to learn more about Dr. Koike and her work.

Jiss Louis, PhD
The RNA Institute, University of Albany, New York, US

Myotonic dystrophy, type 1 (DM1), and type 2 (DM2) are clinically related but genetically distinct neuromuscular diseases. DM1 and DM2 are both caused by the production of expanded repeat-containing toxic RNAs that lead to numerous detrimental cellular outcomes that in turn lead to multi-systemic symptoms. At present, there are no FDA-approved disease-targeting treatments for either DM1 or DM2. The Berglund lab recently identified a class of natural compounds that selectively reduce the toxic RNA with negligible toxicity in multiple models of DM1. Preliminary studies support the activity of the top hit from this class of natural compounds in DM2 patient cells. Unfortunately, most studies focus on DM1, leaving DM2 an understudied disease. Dr. Louis’s study “Determining the therapeutic efficacy of natural compounds in myotonic dystrophy type 2” proposes to evaluate the therapeutic potential of their newly-identified natural lead compound in patient-derived cellular models of DM2. Based on its excellent safety profile, Dr. Louis and colleagues will also perform a combinatorial screen for compounds that synergize with their lead compound. The overall goal of the project is to identify a safe mono- or combination disease-targeting therapy to test in animal models of DM2 that are currently being developed which will help advance the therapeutic pipeline for DM2. Click here to learn more about Dr. Louis and her work.

Emma Shea
University of Florida, Gainesville, Florida, US

Emma Shea’s research project “CRISPR/Cas9-nickase approaches to shrink expanded repeats in myotonic dystrophy” focuses on developing a CRISPR-Cas9 gene editing therapy to shrink the disease-causing expanded DNA sequence. Current myotonic dystrophy (DM) therapeutics in development do not target the DNA sequence directly but instead target molecules further downstream—molecules made from the disease-causing DNA. A therapeutic that directly targets and shrinks the repeats would be beneficial to patients because if successful, it may alleviate symptoms and even slow or prevent disease progression. Using CRISPR to make modifications in disease-causing DNA is an approach that is currently in clinical trials to treat genetic diseases. The traditional Cas9 protein cuts the DNA in two specific places and relies on our cells’ natural repair mechanisms to fix the double-stranded break after a modification has been made. Building on previous work, this project proposes to use the Cas9 nickase variant to make a single cut. The nature of the CRISPR Cas9 system allows for high specificity within the DNA, so that it only cuts at certain sequences. Some previous research directed the Cas9 protein to the repeats. In this project Ms. Shea and her colleagues propose to target the Cas9 to a unique sequence around the repeats. Not only should this reduce the probability of off-target cutting, but this may also enhance repeat contraction due to stabilization properties of one end of the repeat. They aim to identify the best tools and the best locations in the DNA to make the cut and induce repeat shrinking. Click here to learn more about Emma Shea and her work.

In partnership, the Myotonic Dystrophy Foundation US and the Myotonic Dystrophy Foundation UK made the following Research Fellowship grants in 2022:

Lily Cisco
University of Rochester Medical Center, Rochester, New York, US

The overall goal of the study is to better understand the mechanism of skeletal muscle weakness and degeneration in myotonic dystrophy (DM) and to determine if repurposing FDA-approved drugs holds therapeutic promise. The study, “identification of altered muscle calcium handling as a potential DM1 therapeutic target” focuses on better understanding what causes the skeletal muscle aspect of the disease, as well as to identify potential druggable targets for the use as therapies to DM skeletal muscle pathology. A strength to this approach is the ability to determine the role of individual DM associated splice event in isolation, and to cross animals to determine their impact in combination. They have found that the combination of only two altered transcripts results in significant muscle weakness, respiratory dysfunction, and shortened lifespan of mice. With therapeutic targets identified, they look to determine if the use of already FDA-approved drugs can be used to treat the mouse models to rescue skeletal muscle and respiratory phenotypes and extend the lifespan of the DM mouse models. They will expand their studies to a more complex DM mouse model to determine if potential treatments are also effective in a model that more closely mimics the disease mechanism. Click here to read more about Lily Cisco and her ongoing work.

Avery Engelbrecht
University of Florida, Gainesville, Florida, US

The goal of the study, the “characterization of a novel BAC transgenic mouse model for DM2”, is to better understand the contribution of both the toxic RNAs and toxic RAN proteins in myotonic dystrophy type 2 (DM2) by characterizing a new mouse model for DM2. The Ranum Lab has had great success with making two different repeat expansion mouse models, one for ALS and a second for SCA8. This study will characterize novel DM2 mice to provide insight into the role of expansion RNAs and RAN proteins in the disease and hopefully to provide a DM2 mouse model that can be used to test therapeutic strategies. The study will leverage the Ranum Lab’s recently published findings that metformin, a known inhibitor of RAN translation, reduces RAN protein levels and improves disease features in a C9orf72 BAC transgenic mouse model of ALS. To explore the potential therapeutic value of metformin in DM2, they will treat their DM2 mice with metformin and examine changes in the molecular and disease features. Taken together, this study will characterize the first BAC transgenic mouse model of DM2, provide insight into the role of expansion RNAs and RAN proteins in DM2, and provide preclinical testing data on a potential therapeutic approach for DM2. Learn more about Avery Engelbrecht and his work.

Jesus Frias
The RNA Institute, University at Albany, New York, US

Myotonic dystrophy (DM) is caused by repeat expansion mutations that produce toxic expanded repeat RNA that leads to a plethora of downstream effects. The research lab has identified possible lead small molecule therapeutics for DM1. Based on previous work from the Berglund Lab, they have developed a new series of small molecules with improved therapeutic efficiency. They have already identified one lead novel compound that rescues hallmarks of DM in cell culture and animal models. In the study, “determining the therapeutic potential and mechanisms of action of novel small molecule therapeutics for DM1”, they will test the therapeutic potential of additional compounds and determine how these compounds work at the molecular level with the aim of developing more effective therapeutics for the disease and ultimately in addressing the need for treatments for DM. Click here to read more about Jesus Frias and his prior research.

Christina Heil, PhD
University of Rochester Medical Center, Rochester, New York, US

Diagnostic testing for myotonic dystrophy (DM) is needed to provide genetic counseling and prognosis for patients. Current standards have limitations to determining the accurate size of the repeat expansion, and they can fail to detect variant repeats that usually cause milder symptoms. Extremely long repeat expansions found in tissues like skeletal muscle are particularly difficult to analyze. Long-read DNA sequencing is a relatively new and fast advancing technique, that has proven useful in characterizing long repeat expansions but has not yet been widely employed. It is able to not only determine accurate repeat size but also gives information about the full repeat sequence, revealing possible repeat interruptions that might stabilize the repeat expansion. Furthermore, long-read DNA sequencing depicts the heterogeneity of repeat sizes found in a person’s blood sample and can be used to assess repeat instability. The study, “genetic characterization of DM1 models”, plans to use this new technique to study age-dependent repeat instability in DM1 mouse models. They will also study the effects of antisense oligonucleotide treatment. Results will further shed light onto the potential impact of repeat instability on disease progression. Optimized protocols established in this study will help long-read DNA sequencing become a rapid and powerful tool for research and clinical care, aiding better characterization of this repeat expansion disorder and better genetic counseling and prognosis for patients. Learn more about Dr. Heil and her work.

Preeti Kumari, PhD
Massachusetts General Hospital, Boston, Massachusetts, US

The goal of the study, “molecular biomarkers of myotonic dystrophy in cerebrospinal fluid”, is to use cerebrospinal fluid (CSF) samples from myotonic dystrophy (DM) patients to identify markers of brain involvement that can be used to detect early changes in the progression of DM and determine whether new treatments are working. The rationale is that small particles called extracellular vesicles (EVs) are released from many different cell types into the urine, blood, and CSF. EVs contain molecules called extracellular RNAs (exRNAs) that can serve as biomarkers of cancers and other disease states. Their research group was the first to demonstrate that EVs in urine also contain a certain type of exRNA that can serve as specific biomarkers of DM and other muscular dystrophies. Recently, they also have found these exRNAs in the CSF. However, to date relatively little is known about the extent of the changes in exRNA that occur in DM patients as compared to healthy individuals, including the relationship of exRNA markers to the underlying disease state or rate of progression. CSF exRNAs are a rich and renewable biomarker source that has the potential to enable convenient non-invasive monitoring of disease activity and determine at an early stage or whether a new drug is having its intended effect during the course of treatment so that the dose may be adjusted upward or downward as needed. This would speed the evaluation of drug efficacy and decrease the time it takes to have a new drug available for patient use. Learn more about Dr. Kumari and her work.

Larissa Nitschke, PhD
Baylor College of Medicine, Houston, Texas, US

Nitschke’s broad research interest is to investigate the regulation of genes involved in human diseases, with a hope that a better understanding of their regulatory mechanisms will help uncover disease risk factors and guide the way to the development of novel treatment options and therapeutic approaches. Her study “the compensatory mechanism of MBNL proteins and its importance in myotonic dystrophy type 1 (DM1) disease” aims to 1) determine the molecular details by which the MBNL2 protein is increased upon loss of MBNL1, 2) investigate the extent to which the compensatory mechanism counteracts DM1 disease and, 3) test if the mechanism can be extrapolated to improve DM1 symptoms. The study thereby lays the foundation for future studies investigating if the compensatory mechanism can be modulated for therapeutic purposes. Learn more about Dr. Nitschke’s work.

Zoe Scherzer
University of Florida, Gainesville, Florida, US

Excessive sleepiness prevents myotonic dystrophy (DM) patients from being able to hold down jobs, function normally in social situations, and participate in normal relationships. Though sleep problems seen in people with DM are well-documented and established, causes underlying this set of symptoms remain to be discovered. Using a top-down approach to study causes of DM-associated sleep problems, this study, “investigating the contribution of circadian disruption in DM-associated sleep disorders”, will classify the exact profile of these issues starting at a large scale (whole body). They will then investigate individual components within the body (events happening within body cells). This research aims to answer key questions to provide groundwork for future therapeutic interventions. Learn more about Zoe Scherzer’s work.

Xiaomeng Xing
University of Nottingham, England, UK

Xing’s study, the “analysis of DMPK expansion transcript degradation and MBNL–RNA binding kinetics in myotonic dystrophy type 1 (DM1)” has three main aims. The first aim is to work out how cells degrade the mutant expRNAs with a view to making this a focus for future therapeutic approaches. DM is caused by additional DNA sequences which are copied into RNA and then get stuck in the nuclei of patient’s cells. This extra RNA sequences (expansion RNA or expRNA) interact with proteins called MBNL1 and MBNL2 and it is widely considered that this interaction is one of the most important events causing the condition. To understand this, the study will screen multiple enzymes to work out which ones are the most important for degrading the expRNA in patient’s cells. The second aim is to develop a reliable and accurate method to count mutant DMPK transcripts by using new technology. This could have great benefits for many different projects and approaches being developed to treat DM, as it will provide a biomarker (readout) for the primary cause of the condition, the mutant expRNA. Finally, the study will attempt to decode the complex link between MBNL–RNA binding and MBNL function using a new technique called KIN-CLIP, to measure the binding and dissociation kinetics of RNA– MBNL interactions. Learn more about Xiaomeng Xing’s work.

In partnership, the Myotonic Dystrophy Foundation US and the Myotonic Dystrophy Foundation UK made the following Research Fellowship grants in 2021:

Kamyra Simone Edokpolor
Emory University School of Medicine, Atlanta, Georgia, US

A lesser known and understudied symptom of DM1 patients is an increased risk of surgical complications associated with general anesthesia. Many patients fear medical procedures that involve general anesthesia, given that in the most severe cases, complications during the recovery period result in fatalities. Unfortunately, the molecular mechanisms underlying adverse responses to anesthesia in DM1 remain largely unknown. Anesthetics induce and maintain the quiescent state by increasing the production and circulation of the inhibitory neurotransmitter, GABA, throughout the brain, suggesting an enhanced inhibitory mechanism could underlie delayed recovery in DM1. Overall, the goal of the project “MBNL2 Dependent Dysregulation of GABAARs: Implications for CNS Symptoms in Myotonic Dystrophy Type 1” is to reveal new insights into how an RNA mis-splicing event may impact GABA and also interrogate the global effects of MBNL2 on GABA. Identifying how GABA receptors are primarily involved in this pervasive symptom will potentially provide new drug targets to improve DM1 patient care. Learn more about Kamyra Edokpolor’s work.

Maya Gosztyla
University of California, San Diego, California, US    

Maya Gosztyla’s project “Investigating RNA-binding Proteins and RNA Localization in cDM1 Organoids” plans to search for new RBPs, beyond those currently known, that are dysregulated in DM1. They will conduct this analysis using cerebral organoids, which mimic the cells and structure of the human brain using spherical clumps of cells grown in a dish. They will also investigate whether incorrect localization of RNAs within each cell, rather than incorrect RNA processing, contributes to DM1’s cognitive symptoms. These experiments will provide important insights into how DM1 affects the brain and provide new avenues for developing treatments that address its cognitive symptoms. Read more about Maya Gosztlya’s work.

Rong-Chi Hu
Baylor College of Medicine, Houston, Texas, US

Rong-Chi Hu’s project “Mechanisms of DM1 Cardiac Pathogenesis and Potential Therapeutics” will utilize a mouse model developed in the sponsor’s lab to determine the degree to which different molecular mechanisms contribute to DM1 cardiac pathogenesis and to test two different CRISPR-based therapeutic strategies to decrease the expression of CUG repeat RNA in the heart. The completion of this proposal will bring insights into the molecular details of heart pathogenesis and downstream consequences on heart function in DM1, as well as expand upon the limited therapeutic approaches for cardiac aspects of DM1. Read more about Rong-Chi Hu’s work.

Benjamin M. Kidd
University of Florida, Gainesville, Florida, US

DM affects many different tissues throughout the body resulting in muscle wasting, gastro-intestinal problems, sleeping issues, and wide-spread reduction of brain volume. While research studies have focused on disease mechanisms involved in skeletal muscle wasting in this disease, our understanding of the molecular events that lead to this brain loss, or cerebral atrophy, and associated neurological symptoms remain unclear. To address this critical issue, the project “Brain Choroid Plexus Dysregulation and Cerebral Atrophy in DM1” will use several mouse genetic models of DM1 to test the hypothesis that the DM1 mutation has its most profound deleterious effects on a specific cell type in the brain, choroid plexus epithelial cells, which produce the cerebrospinal fluid vital for brain health. Importantly, these cells function in the transport of nutrients into, and the clearance of potentially toxic by-products from, the brain. The goal of the project is to identify novel and accessible cell targets and pathways for effective myotonic dystrophy therapies. Learn more about Benjamin Kidd’s work.

Subodh Kumar Mishra, PhD
The RNA Institute, University of Albany, New York, US

Despite the significant knowledge about the complex pathogenic mechanisms, there are currently no disease targeting FDA-approved treatments for DM. This project identified Centaureidin and four more dietary flavonoids (DFs) that selectively reduce the DM expansion RNA abundance and rescue mis-splicing with negligible toxicity. Due to their excellent safety profile, DFs are well tolerated and often used as dietary supplements. The study “Discovery of Dietary Natural Compounds as Potential Therapeutics for Myotonic Dystrophy (DM)” proposes two main aims; i) assessing the therapeutic potential of these DFs for the promising treatment of DM, and ii) determining their mechanism of action (MOA). The overall goal is to identify new potential therapeutic compounds for DM patients that can reduce or lower the levels of toxic CUG/CCUG RNA abundance with a negligible or manageable toxicity profile. Learn more about Dr. Mishra’s work.

In partnership, the Myotonic Dystrophy Foundation US and the Myotonic Dystrophy Foundation UK made the following grants in 2020:

“Reach DM- Study to Promote Trial Readiness by Genetic Analysis and Telemedicine Assessments”

PI: Johanna Hamel, MD
University of Rochester, New York, US

This project supports Dr. Johanna Hamel and Dr. Charles Thornton at the University of Rochester to study DM1-affected individuals to determine feasibility for remote genetic testing and disease assessments. This study focuses on 300 individuals who have a clinical diagnosis of DM1 in the MDF and National Registries. The goal of this study is to assess phenotype and genotype remotely and improve understanding of disease variability in DM1. By reversing the conventional directionality of research, which involves patients travelling to research centers, they evaluate people in their homes by sending them a toolkit and conducting virtual research visits via tele-video conferencing. By overcoming financial, geographic, and socioeconomic barriers, this study expands access to research and genetic testing.

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In partnership, the Myotonic Dystrophy Foundation US and the Myotonic Dystrophy Foundation UK made the following Research Fellowship grants in 2020:

Raphael Benhamou, PhD
Scripps Research Institute, Florida, US

Dr. Benhamou’s study “Targeting the RNA that Causes DM2 for Degradation with Small Molecules” focuses on inactivating and/or eliminating the DM2 RNA with drug-like small molecules. By engineering small molecules that bind the RNArepeat expansion the goal is to: (i) synthesize potent, selective inhibitors by using the RNA repeat as a template. This on-site drug synthesis approach only occurs in DM2-affected cells, leaving healthy cells unexposed to the active drug; and (ii) cleave the RNA, thereby eliminating the toxin from DM2-affected cells altogether. Each compound type will be fully evaluated in DM2 patient-derived fibroblasts and fibroblasts from healthy donors. These groundbreaking approaches have the potential to establish a completely new paradigms for designing small molecules that target toxic structured RNAs implicated in DM2 disease.

Talita Conte, PhD
University of Montreal, Canada

Dr. Conte’s study “Novel strategy targeting muscle stem cells as a therapeutic approach for myotonic dystrophy type 1” proposes to use a new class of drugs that has shown encouraging results improving the muscle function of different degenerative conditions, such as aging. These drugs act by eliminating specifically dysfunctional cells and leaving only the competent cells to restore muscle function and regeneration. Thus, the study first proposes to screen a variety of these drugs on the muscle stem cells of patients affected by DM1 to find the most potent one. They plan to validate the lead compound in vivo on a mouse model of DM1 to evaluate its effect on muscle function. Overall, the research plan proposes to target muscle stem cells as a new therapeutic approach to mitigate DM1. This novel field of research has shown promising results in other degenerative conditions (aging) but it has not been explored in DM1. Therefore, it will bring new perspectives to patients affect by DM1 who have very limited pharmacological options to improve their quality of life.

Jana Jenquin, PhD
University of Florida, Gainesville, Florida, US

The goal of the first two aims of Dr. Jenquin’s study “Improving the activity of diamidines for potential therapeutic use for patients with myotonic dystrophy types 1 and 2” is to characterize our current lead small molecule by assessing how well, and by what mechanism, it rescues DM-associated molecular markers in DM1 and DM2 cell and animal models. The third aim of the study is to synthesize more compounds related to the lead compound with an emphasis on compounds predicted to cross the blood brain barrier to potentially address the cognitive symptoms associated with DM and continue to improve these compounds as potential therapeutics. The goal of the study is to get the best in class of these compounds into clinical trials for DM1 and DM2 to help patients and their families.

Sarah Overby
Incliva, University of Valencia, Spain

The study “Restoration of MBNL proteins through miRNA blocking as DM1 therapy” will use antisense oligonucleotides (ASOs) to target a different type of DNA called micro RNAs (miRNAs) by binding on the MBNL RNA transcripts. This way, miRNAs are blocked from binding there and the transcript is free to be translated into protein. This is a promising strategy because it does not need a high concentration of blockmiRs to deliver to this part of the cell. Subsequently, this could lead to less unwanted off-target effects. This technique has already shown positive results in DM1 cells by increasing the production of MBNL protein in the rest of the cell and rescuing some of the downstream functions that the trapped MBNL cannot perform. The specific aims of the study are to 1) evaluate blockmiRs administered to HSALR mice to determine if the therapeutic effects are similar to those observed in DM1 myoblasts and 2) develop and evaluate of P-PMO BlockmiRs in DM1 myoblasts.

In partnership, the Myotonic Dystrophy Foundation US and the Myotonic Dystrophy Foundation UK made the following grants in 2019:

“Developing novel CRISPR-Cas9 variants for efficient in vivo contraction of CTG/CAG repeats”

PI: Vincent Dion, PhD
Cardiff University, Wales, UK

Gene editing, a way to correct the mutation that causes DM1, provides novel research avenues. Recently, Dr. Dion’s team showed that CRISPR-Cas9, an unparalleled gene editing technology, can contract precisely the expanded CTG/CAG repeat tract, thereby removing the cause of DM1. They found that gently nicking the repeat tract leads to contractions. Administration of the enzyme is difficult and inefficient because it is too large to be packaged into adenoassociated viruses, the delivery method of choice for gene therapies. In this project, they aim to improve the efficiency of Cas9 delivery by reducing the size of the enzyme and to determine its safety by measuring the frequency of unwanted mutations it might cause. Dion will test new Cas9 variants both in human cells and in pre-clinical mouse models. They aim to develop a safe and efficient tool for an eventual therapy based on gene editing.

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In partnership with the Myotonic Dystrophy Foundation US, the Myotonic Dystrophy Foundation UK made the following Research Fellowship grants in 2019:

Carl Shotwell
University of Florida, Gainesville, Florida, US

The goal of Mr. Shotwell’s project “Engineering Synthetic RNA Binding Proteins to Probe the Mechanisms of Myotonic Dystrophy and Development of Potential New Therapeutics” is to design and identify synthetic proteins that displace endogenous Muscleblind (MBNL) from binding to expanded CUG (DM1) and CCUG (DM2) repeats and thereby rescue splicing without off-target effects of some other putative treatment strategies. The specific aims of the project are to: (1) determine the minimal domains required for a functional MBNL1 protein for splicing regulation and (2) create synthetic MBNL1 proteins with enhanced binding to toxic CUG/CCUG-expanded RNA. The first aim is designed to better understand the functional regions (domains) of MBNL protein, while the second aim exploits that knowledge to design synthetic proteins with potential therapeutic value.

Shruti Choudhary, PhD
Scripps Research Institute Florida, US

In Dr. Choudhary’s project “Selective and non-toxic small molecules that cleave r(CUG) repeats in DM1—optimization and evaluation as a therapeutic approach” she proposes straightforward studies to develop small molecules that recognize long, pathogenic CUG repeats in DMPK over smaller, non-pathogenic lengths. The rationale is that small molecules targeted in this fashion may be more selective than oligonucleotide drugs currently in development which may or may not be able to distinguish between short and disease causing repeats. The work focuses on optimizing and testing a small molecule drug based on the bleomycin scaffold. The specific aims are to: (1) optimize the bleomycin-cleavage module, (2) study compound potency and selectivity in DM1 patient-derived cell lines, and (3) evaluate the efficacy of the best compounds in a mouse model of DM1.

In partnership, the Myotonic Dystrophy Foundation US and the Myotonic Dystrophy Foundation UK made the following grants in 2018:

“Myotonic Dystrophy Clinical Research Network (DMCRN) Site Grants: Multicenter Study of Natural History and Genetic Modifiers in Myotonic Dystrophy Type 1”

PI: Nicholas Johnson, MD
Virginia Commonwealth University, Virginia, US

The DMCRN will undertake an ambitious 8-site study of disease progression and genetic modifiers of DM1. The proposed study will use unrestrictive entry criteria, ensuring that any subject with DM1 is included. To meet the increased recruitment demands, the study involves new sites (University of Utah, Salt Lake City and Houston Methodist Neuroscience Institute, Houston, TX) and concise study visits (2-3 hours) that do not include invasive procedures. It is expected that this will drive strong enrollment and allow participation from segments of the community who previously may have felt disenfranchised. As compared to the current study, it examines a larger number of patients (n = 500) over a longer time period (2 years). The outcome measures are a subset of those used in previous studies, selecting those with best performance characteristics. Sites and partners include:

Tetsuo Ashizawa, MD, Houston Methodist Neuroscience Institute, US

John Day, MD, PhD, Stanford University, US

Nicholas Johnson, MD, University of Utah, US

John Kissel, MD, Ohio State University, US

Jeffrey Statland, MD, University of Kansas Medical Center, US

S.H. Subramony, MD, University of Florida, US

Laurie Gutmann, MD, University of Iowa, US

“Development of a Mouse Drug Testing Facility for Myotonic Dystrophy”

PI: Laurent Bogdanik, PhD
The Jackson Laboratory, Bar Harbor, Maine, US

The reliable evaluation of drug candidates upstream of clinical trials relies in most cases on good mouse models that replicate key features of the disease, but also on reliable experimental assays. A robust infrastructure to produce, maintain, distribute and study mouse colonies, connect with drug developers, and prepare and execute in vivo pharmacology studies in a rigorous laboratory environment are also desirable. The goal of Dr. Bogdanik’s project is to make available to the DM drug development community, in a centralized location, the HSA-LR model and future DM mouse models, along with the knowledge resources and the drug testing services that will support the development of tomorrow’s cures.

“Request for Support for Publication and Open Access Fee for a Peer-Reviewed Myotonic Dystrophy Therapy Review Paper”

PI: Ruben Artero, PhD
University of Valencia, Spain

The depth and quality of DM publications, from basic research to review papers, is an essential component to attracting more research and industry engagement to the field. DM publications in high impact journals and in journals with a broad readership, is one of the most effective ways to highlight the disease and unmet need. It is also an effective method to attract a more diverse research base. Dr. Ruben Artero, a well-respected researcher in the myotonic dystrophy field from the University of Valencia, Spain, received a one-time grant to support the publication and open access fees for a review article entitled “Oligonucleotide-based therapies for Myotonic Dystrophy”. The article will be published in Drug Discovery Today.

“Meeting Grant Support for 9th International Conference on Unstable Microsatellites and Human Disease”

PI: Laura Ranum, PhD
University of Florida Continuing Medical Education, US

9th International Conference on Unstable Microsatellites and Human Disease.

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In partnership with the Myotonic Dystrophy Foundation US, the Myotonic Dystrophy Foundation UK made the following Research Fellowship grants in 2018:

Ashish Rao
Baylor College of Medicine, Houston, Texas, US

Mr. Rao’s project “Tissue specific expression of expanded CUG repeat RNA to investigate the cardiac pathogenesis of myotonic dystrophy type 1” aims to establish a new animal model for DM1 cardiac disease for use in the field, improve the current understanding of molecular events contributing to the cardiac symptoms in DM1 patients, and evaluate the feasibility of a novel methodology for treatment of cardiac manifestations in DM1.

Florent Porquet
University of Liege, Belgium

Mr. Porquet’s project “CRISPRI-induced transcriptional silencing of DMPK as a therapeutic strategy against myotonic dystrophy type 1” aims at elaborating a new curative approach which has never been tested before in DM1. Their strategy consists in the use of molecular guide (named CRISPRi system) derived from the recent CRISPR/Cas9 system breakthrough. They will use this guide in order to prevent the production of the molecular defect causing the disease.

Curtis Nutter, PhD
University of Florida, Gainesville, Florida, US

The goals of Dr. Nutter’s project “Congenital myotonic dystrophy: pathomechanism and therapeutic development” are to investigate how a key RNA processing factor specific to early development may contribute to the symptoms of congenital myotonic dystrophy (CDM), and test potential treatments using drugs called antisense oligonucleotides (ASOs) to correct RNA processing defects that lead to symptoms of CDM.

Kiruphagaran Thangaraju, PhD
University of Florida, Gainesville, Florida, US

The goal of Dr. Thangaraju’s project “Molecular characterization of RNA and RAN protein effects in DM2” is to generate a mouse model of DM2 that will allow us to better understand the contribution of both the mutant RNAs and mutant RAN proteins. To accomplish this, he will isolate and use a large piece of human DNA that contains all of the normal regulatory sequences. This method will help ensure that the RNAs and RAN proteins are made in the correct way of the mouse body, including the brain, to mimic the human disease.

In partnership, the Myotonic Dystrophy Foundation US and the Myotonic Dystrophy Foundation UK made the following grants in 2017:

“Houston Methodist Coordinator Position Grant”

PI: Tetsuo Ashizawa, MD
Houston Methodist Neurological Institute, US

The Myotonic Dystrophy Foundation will provide Houston Methodist Neurological Institute with funds to support a clinic coordinator position at the Ashizawa Lab.

“Biomarker Qualification Project”

Jane Larkindale, DPhil
Critical Path Institute, US

The Critical Path Institute will provide the Myotonic Dystrophy Foundation (MDF) with support with a regulatory strategy for a Drug Development Tool (DDT) qualification pathway for a biomarker for myotonic dystrophy (DM), preparation and regulatory review of submissions to the FDA, support for all interactions with regulators, including preparations for meetings of Biomarker Qualification Review Team (BQRT) and leadership at FDA meetings, as well as keep the MDF updated on all regulatory developments (guidance, webinars, meetings) related to qualification in general and DM and other related neurological disorders in particular.

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In partnership with the Myotonic Dystrophy Foundation US, the Myotonic Dystrophy Foundation UK made the following Research Fellowship grants in 2017:

Anwesha Banerjee, PhD
Emory University, Atlanta, Georgia, US

Dr. Banerjee’s project “Mechanism of CNS-associated behavioral dysfunction in novel mouse model of Myotonic Dystrophy Type 1” aims to understand underlying molecular mechanisms causing the CNS-associated deficits of DM1. This basic research is anticipated to facilitate the development of disease mechanism-targeted therapeutic interventions in DM1 patients. The goal is to develop a new mouse model to study brain dysfunction and provide new mechanistic insights into CNS-associated behavioral symptoms in myotonic dystrophy. The study also seeks to provide proof of concept that antisense oligonucleotides can restore brain function in DM1.

Kaalak Reddy, PhD
University of Florida, Gainesville, Florida, US

The goal of Dr. Reddy’s research proposal, “Pre-clinical investigations of small molecule-mediated targeting of toxic RNA production in DM2” is to evaluate a novel therapeutic strategy aimed at reducing the production of toxic RNA. In collaboration with members of the Berglund and Ranum laboratories, Dr. Reddy will characterize the therapeutic properties of several small molecules that were recently shown in the Berglund lab to inhibit the production of the toxic DM1 and DM2 RNA and test the efficacy of the most promising lead compound panel in DM2 human cell and mouse models. The study will help determine if lead compounds recently identified in the Berglund laboratory can be developed as treatments for DM.

In partnership, the Myotonic Dystrophy Foundation US and the Myotonic Dystrophy Foundation UK made the following grants in 2016:

“PicnicHealth Registry Project”

PI: Noga Leviner
PicnicHealth, San Francisco, California, US

This is a proposal to design and execute on a pilot project to 1) collect medical records and 2) structure medical record data for a cohort of 100–200 myotonic dystrophy patients using PicnicHealth’s patient-centered medical records collection and management platform. This pilot study will determine whether the approach is a feasible one for constructing DM patient natural histories.

“Prevalence of Myotonic Dystrophy”

PI: Nicholas E. Johnson, MD
University of Utah, US

This project is a Population-Based Prevalence Study in Myotonic Dystrophy Type-1 and Type-2. The prevalence of myotonic dystrophy type 1 and type 2 are unknown. This is at least partly due to the wide variation in the age of onset and individuals with the disease who have not been diagnosed; both of which would not be accounted for in a traditional prevalence study. To address this issue MDF US and MDF UK issued a two-phase RFA. The phase I RFA was designed to develop an assay that could be used in a population-based screen. The phase II RFA provides funds sufficient to implement a screen in a group representative of the general population, for example, via newborn bloodspots or via banked blood from other ongoing studies as appropriate. In phase I, Dr. Johnson was awarded a grant to develop and validate a cost-effective screening methodology capable of estimating the prevalence of DM1 and DM2 mutations and pre-mutations in the general US population. In phase II, Dr. Johnson’s application received the grant award to use a population sample of de-identified newborn blood spots to determine carriers of DM mutations and pre-mutations. This will provide the first-ever large-scale population-based prevalence study of myotonic dystrophy types 1 and 2.

“Workshop Support – Myotonic Dystrophy: Developing a European Consortium for Care and Therapy”

PI: Alexandra Breukel, PhD
European Neuromuscular Centre, Netherlands

This Myotonic Dystrophy Foundation US and the Myotonic Dystrophy Foundation UK-supported workshop was focused on establishing a mechanism for international collaboration between expert centers in Europe in order to ensure better coordination for DM clinical trials. Participating centers would share existing, partly unpublished natural history data, refine suitable outcome measures, provide for identification of patient populations and qualify trial sites. Moreover, the establishment of networking of the existing knowledge, infrastructure and personnel would facilitate appropriate inclusion and communication of patients and patient organizations, the interaction with commercial as well as academic trial sponsors and the involvement of regulators and payers along the translational pathway. Foundation interests in this effort include establishing strong partnerships between the new European consortium and the existing Myotonic Dystrophy Clinical Research Network (DMCRN) in the US.

“Building a Better Mouse”

PI: Cathleen Lutz, PhD
The Jackson Laboratory, US

This project will support the development of a new BAC transgenic mouse model of myotonic dystrophy type 1 (DM1) at the Jackson Laboratory (JAX). This will be accomplished by creating a BAC transgenic with a large CTG repeat and a wildtype control. The funding provided will be used to create the model with some baseline clinical observations of weight, survival and overt phenotypes. Using a BAC approach to express the expanded repeat in all tissues will increase the probability of emulating the multi-systemic nature of DM by showing defects in the CNS, heart and other organ systems, as well as muscle. In addition to the need for new models to better understand disease mechanisms, industry views a better DM1 mouse model as essential to its therapeutic development efforts.

“Extracellular RNA as Biomarkers of Myotonic Dystrophy”

PI: Thurman Wheeler, MD
Massachusetts General Hospital, US

A new drug for treatment of DM1 is being tested in clinical trials. Monitoring drug effects currently requires that patients undergo multiple muscle biopsies, a procedure that is invasive, painful and, in pediatric patients, requires general anesthesia. The goal of this project is to develop biomarkers in human urine or blood that:

Will reduce or eliminate the need for muscle biopsies to determine whether treatments are working
Can be measured multiple times as needed during the trial
Enable inclusion of children with DM1 in upcoming trials

The approach will be applicable to many different treatment strategies for both DM1 and DM2.

“DM Cell Line Library”

PI: Michael Sheldon, PhD
RUCDR Infinite Biologics, Rutgers University, US

This grant award is intended to support the development of eight new DM iPSC lines at RUCDR Infinite Biologics for distribution to qualified investigators at academic institutions and biotech/pharmaceutical companies. Numerous companies seeking to develop therapies for DM have reported that they are having difficulty obtaining well-documented cell lines for DM1 and DM2. High-throughput screening programs for small molecule development in other neuromuscular diseases have found results that differ based upon the cell type used in the screen. By making human iPSC cells derived from fibroblasts of patients with expanded repeats (>400) available, researchers and drug developers will be able to derive cell types (e.g. neurons, myocytes, cardiomyocytes) appropriate to their needs. There will be no licensing fees or reach-through on intellectual property, ensuring that commercial development efforts are unhindered.

“Myotonic Dystrophy Clinical Research Network (DMCRN) Site Grants: Multicenter Study of Natural History and Genetic Modifiers in Myotonic Dystrophy Type 1”

During the last project period, the DMCRN completed its first project, a study of natural history and RNA biomarkers in 100 patients with DM1. The DMCRN subsequently expanded the enrollment and expects to have one year follow up data on 100 subjects by the first quarter of 2017. The results of the DMCRN collaboration abundantly confirmed that RNA splicing biomarkers are tightly linked to the disease process and reliable for monitoring disease activity. The methods and data will be taken forward to the FDA for formal qualification of splicing biomarkers as drug development tools for DM1. The DMCRN is now pursuing parallel work for DM2.

The DMCRN will undertake an ambitious 8-site study of disease progression and genetic modifiers of DM1. The proposed study will use unrestrictive entry criteria, ensuring that any subject with DM1 is included. To meet the increased recruitment demands, the study involves new sites (University of Utah, Salt Lake City and Houston Methodist Neuroscience Institute, Houston, TX) and concise study visits (2-3 hours) that do not include invasive procedures. It is expected that this will drive strong enrollment and allow participation from segments of the community who previously may have felt disenfranchised. As compared to the current study, it examines a larger number of patients (n = 500) over a longer time period (2 years). The outcome measures are a subset of those used in previous studies, selecting those with best performance characteristics.

Six DMCRN site awards have been issued (two DMCRN sites – the National Institutes of Health: Ami Mankodi, M.D., and the University of Rochester, Drs. Richard Moxley III, M.D, and Charles Thornton, M.D., – have separate funding sources):

Tetsuo Ashizawa, M.D., Houston Methodist Neuroscience Institute, US
John Day, M.D., Ph.D., Stanford University, US
Nicholas Johnson, M.D., University of Utah, US
John Kissel, M.D., Ohio State University, US
Jeffrey Statland, M.D., University of Kansas Medical Center, US
S.H. Subramony, M.D., University of Florida, US
Laurie Gutmann, M.D., University of Iowa, US

“PHENO-DM1- Myotonic Dystrophy type 1 (DM1) deep phenotyping to improve delivery of personalized medicine and assist in the planning, design and recruitment of clinical trials”

PI: Hanns Lochmüller, MD
Newcastle University, UK

Myotonic dystrophy type 1 (DM1) is the most common adult-onset muscular dystrophy. The multisystemic phenotype may be highly variable between patients and therefore the selection of appropriate endpoints for therapeutic trials is of great importance for trial readiness. Newcastle University and University College London are working together to deep-phenotype 200-400 DM1 adult patients in the UK and investigate potential biomarkers and skeletal muscle MRI over 9-12 months. The team is currently funded through a UK National Institute for Health Research grant. The on-going study represents an opportunity to leverage the existing funding and data in order to obtain detailed, long-term (24 month) phenotypic data from a large DM1 cohort. Funding from MDF UK, in partnership with MDF US, will extend the study for an additional 18 months, thereby providing extensive natural history data that will be invaluable in design of clinical trials in DM1.

“Development of Magnetic Resonance Imaging as an Endpoint in Myotonic Dystrophy Type 1”

PI: Donovan Lott, PhD
University of Florida, US

Magnetic Resonance Imaging (MRI) has been very useful in examining the muscles of people with different diseases, and it should be important for assessment of people with myotonic dystrophy type 1 (DM1). The goal of this study is to develop MRI of the legs and arms for people with DM1 so that MRI can be used as an endpoint in clinical trials. Specifically, Dr. Lott and team will use MRI to measure different ways the DM1 disease affects muscles and will examine how those measures relate to walking, balance, falls, strength, and arm function.

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In partnership with the Myotonic Dystrophy Foundation US, the Myotonic Dystrophy Foundation UK made the following Research Fellowship grants in 2016:

Ian DeVolder, PhD
University of Iowa, US

In his research proposal titled „Structural and Functional Connectivity in the Brains of Patients with Adult and Late Onset Myotonic Dystrophy Type 1 (DM1): A Potential Biomarker for Disease Progression,“ Dr. DeVolder seeks to find differences in how the brain looks and functions in DM1. He speculates that these differences can provide a good marker of how much the disease has affected a person and may enable people with DM to be treated before the brain changes happen and prevent them altogether. Dr. DeVolder has two specific aims: 1) Look at the structure and function of the brain in patients with DM1 and 2) See whether changes in the brain are directly related to changes in thinking, behavior, number of repeats in the gene, and how long the person has had the disease.

Melissa M. Dixon, PhD
University of Utah, US

Dr. Dixon’s research proposal, “Evaluation of Functional Connectivity as a Brain Biomarker in Congenital Myotonic Dystrophy”, aims to use specialized pictures of the brains of 20 children with congenital myotonic dystrophy (CDM) to look for brain differences compared to children without CDM, to see how their brain structure may change over time. She will also try to determine if brain differences are related to CDM symptoms such as intellectual disability or behavioral problems. Dr. Dixon hopes that the study may help doctors better understand the CDM brain, and how special MRI images may be used in the future to diagnose CDM or measure how a drug might improve those connections in the brain.

Benjamin Gallais, PhD
Universite de Sherbrooke, Canada

Dr. Gallais, in his research proposal, “A 14‐year Longitudinal Study of Cognition and Central Nervous System Involvement in Adult and Late‐onset Phenotypes of Myotonic Dystrophy Type 1,” will pursue a unique opportunity to continue the largest longitudinal study over the longest period in patients with the adult and late onset phenotypes. The research team has already conducted a study on a very large sample over a 9 year period, with strong results on the progression of intellectual and cognitive abilities. The current project aims to extend the follow-up period and answer such questions as how do symptoms progress over time? Do they progress in similar fashion among all patients? What is the rate of progression? Will cognitive involvement progress to dementia? What assessment tool will best permit to assess change in a clinical trial over time?

Ginny R. Morriss, PhD
Baylor College of Medicine, Houston, Texas, US

In myotonic dystrophy, changes to the levels of two proteins, functional MBNL and CELF1, result in defects in expression and processing of RNA targeted by these proteins. Dr. Morriss’ research proposal, “Mechanisms of Skeletal Muscle Wasting Caused by Expanded CUG Repeat RNA”, is aimed at determining the role the protein CELF1 plays in progression of skeletal muscle wasting in DM by examining the extent to which muscle fiber defects and wasting can be reversed by CELF1 depletion (Aim 1) and to identify additional changes in gene expression and RNA processing and changes to signaling pathways that are important to skeletal muscle wasting (Aim 2). A detailed understanding of causes underlying muscle wasting may potentially aid in development of therapies with the hope of correcting muscle wasting in DM1 patients.

Laura Valentina Renna, PhD
IRCCS-Policlinico San Donato, Italy

Dr. Renna’s research proposal, “A New Approach of Pathomolecular Mechanism in Myotonic Dystrophy Insulin Resistance by Nutrigenomics,” aims to investigate the mechanisms that induce insulin resistance in DM patients and whether these mechanisms may contribute to muscle weakness. The results will lead to the identification of novel biomarkers that could be targets for therapeutic intervention. Dr. Renna will also investigate the ability of natural insulin mimetic compounds that are important component of many foods to modify insulin resistance and muscle atrophy in DM.

Lukasz Sznajder, PhD
University of Florida, Gainesville, Florida, US

Dr. Sznajder, in his proposal “Myotonic Dystrophy Type 2: Mouse Models, Pathomechanism and Therapy”, plans to use recently developed techniques in genetic engineering to generate novel mouse models for DM2. These new mouse models will be thoroughly characterized to determine if they faithfully recapitulate DM2 disease manifestations and allow for the study of the molecular events that underlie DM2 disease progression. These DM2 mouse models will be employed to develop a therapy for DM2 based on drugs called antisense oligonucleotides, which are currently being tested in clinical trials for DM1.

In partnership, the Myotonic Dystrophy Foundation US and the Myotonic Dystrophy Foundation UK made the following grants in 2015:

“Inhibiting transcription of CUG/CCUG expanded repeats with small molecules”

PI: Andy Berglund, PhD of the University of Florida
PI: Paul August, PhD of Sanofi

The pharmaceutical company Sanofi and the University of Florida have been awarded a grant the Myotonic Dystrophy Foundation US and the Myotonic Dystrophy Foundation UK to screen for new drugs to treat DM1 and DM2. The University of Florida will be optimizing an assay designed to identify compounds that inhibit the transcription of the repeats in the DM1 and/or DM2 genes, and then will work with Sanofi to conduct a high throughput screen to identify drug candidates. This work builds on a previous discovery by Dr. Berglund and colleagues that the antibiotic actinomycin D can block transcription of CUG repeats at nanomolecular concentrations.

“Assay Development for a Study of Genetic Prevalence in Myotonic Dystrophy”

Nicholas Johnson, PhD
University of Utah, US

Dr. Johnson’s research proposal will lead to a better understanding of the prevalence of the disease-causing mutation or premutation in DM1 and DM2 in the general population, specifically in the US where disease prevalence information is lacking. Accurate information regarding how many people in the US have DM1 and DM2 mutations, or are at risk of repeat expansion, will improve service provision, basic research, drug development and policymaking related to DM. In the first phase of this RFA award, Dr. Johnson will develop and validate a cost-effective screening methodology capable of estimating the prevalence of DM1 and DM2 mutations and pre-mutations in the general US population.

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In partnership with the Myotonic Dystrophy Foundation US, the Myotonic Dystrophy Foundation UK made the following Research Fellowship grants in 2015:

Dr. Ranjan Batra, PhD
University of California, San Diego, California, US

Dr. Batra’s research proposal, “Studying Genome-Wide MBNL-RNA Structure Interactions in Neuronal Development and DM,” seeks to identify genome-wide MBNL-preferred RNA structure motifs for the MBNL (muscleblind) protein family. Evidence suggests that MBNL proteins may bind to certain RNA structures (like a lock and a key). Identifying the RNA structures (locks) that the MBNL (keys) recognizes is important for designing drugs that are able to identify the RNA structures even in the absence of MBNL, as is the case in DM. Dr. Batra’s project will utilize cutting-edge high-throughput RNA-structure surveying techniques and a neuronal development model to study detailed MBNL and RBFOX structural and functional overlap important for proper brain development and function.

Dr. Viachaslau Bernat, PhD
Scripps Research Institute Florida, US

Dr. Bernat’s research proposal, “Precise Lead Therapeutics for Myotonic Dystrophy via in cellulo Synthesis,” plans to develop drug-like small molecules to study and manipulate DM1 toxic RNA. Expanding on Dr. Matthew Disney’s work in developing small molecules to target DM2 RNA, Dr. Bernat’s research will provide a chemical tool to study the effect of the DM1 RNA on cell biology. The project also hopes to provide a diagnostic tool for DM1 that could ultimately help measure disease improvement after therapeutic treatment and may result in a pre-clinical candidate to treat DM1.

Dr. Melissa Hinman, PhD
University of Oregon, Eugene, Oregon, US

Dr. Hinman’s research proposal, “An Investigation of the Cellular and Microbial Etiologies of Gastrointestinal Pathologies in Myotonic Dystrophy Zebrafish,” aims to provide insight into the GI symptoms of myotonic dystrophy using DM zebrafish models. The majority of people living with DM report GI symptoms and many of them have higher than normal bacteria levels in parts of their intestines. Researchers have created zebrafish models with RNA and protein changes similar to those causing DM in humans, and young zebrafish are uniquely suited to studying digestive processes as their internal organs can be seen through their transparent bodies. Dr. Hinman’s research will first determine which cell types are responsible for digestive symptoms in the DM zebrafish. Her research will then compare the number and type of bacteria found in the affected fish with healthy fish in order to determine what role bacteria play in DM digestive symptoms with an aim to develop new ideas for potential therapies.

Jintang Du, PhD
Scripps Research Institute, La Jolla, California, US

Dr. Du’s research will seek to develop DNA-binding Py-Im polyamides (macromolecules with repeating units) to bind specific, identified CTG-CAG triplet repeats that cause DM1. Dr. Du and his lab partners have established that a specific Py-Im polyamide targeting CTG-CAG triplicate repeats is able to virtually abolish nuclear foci in patient cells. The molecule does not affect genes with short, non-pathogenic CTG/CAG repeats. Dr. Du will also investigate the pharmacokinetics, maximum tolerated dose and tissue distribution of the most effective molecules. Studies will be conducted on mouse models.

Yao Yao, PhD
The Rockefeller University, New York, New York, US

Dr. Yao’s research involves stem cells, and will seek to understand how pericytes (multipotent stem cells) can be used to treat DM. His research project will include investigating how laminin, which covers pericytes (stem cells) in normal conditions but degrades in disease conditions, affects specific functions of these stem cells. To this end, Dr. Yao will use a laminin-deficient mouse model he has developed, which shows severe muscular dystrophy soon after birth, similar to what is observed in congenital myotonic dystrophy. In addition to understanding the role of laminin on pericyte stem cell health and function, Dr. Yao will also investigate the mechanisms that drive laminin loss, and attempt to identify targets to control pericyte stem cell function and laminin loss in order to treat myotonic dystrophy and other muscular dystrophies.

Ayal Hendel, PhD
Stanford School of Medicine, Stanford, California, US

CTG/CAG repeat tracts represent the genetic basis for more than a dozen inherited dominant neurological disorders including Myotonic Dystrophy type 1 (DM1) and Huntington’s disease that currently have no cure.  Despite the multitude pathologies underlying these devastating disorders, they all share common etiology: the expansion of CTG/CAG repeats. Interestingly, expanded CTG/CAG repeats have been shown to be prone to double-strand breaks (DSBs).  Moreover, it was shown that the repair of the DSBs leads mainly to repeat contractions. These findings suggest that controlled DSBs might provide a way to induce repeat contractions that will correct disease-causing mutation and reduce disease risk. Dr. Hendel’s research will harness a unique genome editing technology in combination with induced pluripotent stem cells to examine the contribution of DSB repair to the stimulation of repeat contractions in DM1 cells, ultimately exploring new cellular and molecular DM1 pathological mechanisms involved in myotonic dystrophy.

Suzanne Rzuczek, PhD
Scripps Research Institute Florida, US

Dr. Rzuzcek, in conjunction with the Disney Lab of The Scripps Institute, plans on using small molecules to disrupt the interaction between repeating CUG RNA and MBNL1 (muscleblind-like 1 protein), freeing it to function normally. The Disney Lab, of which Dr. Rzuczek is a member, has designed and synthesized several compounds that specifically bind the expanded CUG RNA and disrupt the interaction with MBNL1 in vitro. These compounds contain CUG-binding small molecules tethered together by a spacer. This approach is called modular assembly. Recently the spacer has been optimized to increase bioactivity and cell uptake. Dr. Rzuczek and her colleagues will improve the activity of the modularly assembled compounds using two approaches. The first will use the repeating DM1 RNA as a template to assemble small compounds with their optimized spacer into large modularly assembled structures within cells. This process is known as in situ click chemistry. The second approach will screen many small molecules that are similar to the known binders of DM1 RNA. Hit compounds will be screened in cells using a method that detects low levels of bioactivity. Compounds that are active in cells will be modularly assembled on the Disney-optimized spacer to enhance the interaction with DM1 RNA and improve bioactivity. If successful, these compounds could become a treatment for myotonic dystrophy.

Micah Bodner, PhD
University of Oregon, Eugene, Oregon, US

Dr. Bodner’s research, “Therapeutic Agents for Myotonic Dystrophy; Defining the Pharmacophore of Pentamidine,” under the guidance of Dr. John Andrew Berglund, Ph.D., at the University of Oregon, will continue the study of a potential therapeutic drug, pentamidine, which was recently identified by the University of Oregon. Pentamidine is a promising lead compound for treatment of DM. Pentamidine and compounds like it have been used to reverse symptoms of DM in cell and mouse models of the disease and even alleviate myotonia in mice. However, some obstacles must be overcome before a pentamidine-based compound can be used clinically. The obstacles include: a lack of evidence for how pentamidine elicits the therapeutic effect; lack of oral availability; lack of central nervous system (CNS) activity; and toxicity. The experiments proposed in Dr. Bodner’s research plan are designed to increase understanding of how pentamidine functions and how to manipulate it in order to make a useful DM therapeutic that is orally available, CNS active and non-toxic. The information gained from these experiments will also be used to design other compounds similar to pentamidine to better understand what portions of the compound promote binding to the RNA fragment. These compounds will then be used in DM cell and mouse model testing to understand how they perform in tests and whether they are tolerated by the cells and animals.

Nicholas Johnson, MD
University of Rochester Medical Center, Rochester, New York, US

Dr. Johnson’s research, “Characterization of Symptoms and Development of a Disease Specific Instrument for Congenital and Juvenile Myotonic Dystrophy,” under the guidance of Dr. Chad Heatwole, M.D. at the University of Rochester Medical Center in Rochester, New York, will study the severe congenital and juvenile onset forms of myotonic dystrophy. Currently, there is very little information about the most critical symptoms associated with these forms of the disease. There are anecdotal reports that indicate that the issues important to patients with early onset myotonic dystrophy are different from those experienced by adult onset myotonic dystrophy patients. In addition, to date no significant research has been conducted to study the impacts of promising adult-onset DM therapies in congenital and juvenile-onset populations. This project will collect survey data from children and their parents describing and prioritizing the effects of the disease on the children’s cognitive, physical, and emotional health. This data will be used to create an instrument measuring quality of life for this population, both with respect to the impact of key DM issues and of current adult-onset treatments on key issues affecting congenital and juvenile-onset DM patients and their family members.

Zhihua (Tina) Gao, PhD
Baylor College of Medicine, Houston, Texas, US

Dr. Gao’s research, “Development of Therapeutic Approaches to Silence CUG Expansion RNA in Myotonic Dystrophy Mouse Models Using Recombinant Adeno-associated Virus,” under the guidance of Dr. Thomas Cooper, M.D., at Baylor College of Medicine in Houston, Texas, will use a virus that has been modified for therapies of other muscular dystrophies to carry elements that can remove the toxic RNA in myotonic dystrophy mouse models. The effective therapeutic approach developed in the mouse model holds a potential for future clinical trials in DM1 patients. Myotonic dystrophy is caused by an unusual genetic mutation in which a small DNA segment of the mutated gene is repeated hundreds of times. DNA, in the form of chromosomes, is in the nucleus of a cell. When there is a need, DNA is copied into RNA. RNA then moves from the nucleus to the cytoplasm of the cell to deliver the genetic message. In myotonic dystrophy, the mutated gene is copied into RNA, but the RNA is trapped in the nucleus because of the repeated segments. The RNA then builds up in the nucleus and creates problems that disrupt the functions of many other genes. The RNA with repeated segments therefore becomes very toxic.

By forcing the expression of the mutated gene with hundreds of repeated segments in mouse skeletal muscle and heart, researchers have mimicked the DM1 (type 1) disease in mice. The goal of Dr. Gao’s proposal is to develop a recombinant adeno-associated virus (rAAV) vector-based strategy to clear away the toxic RNA in the DM1 mice. Dr. Gao’s sponsoring facility, the lab of Dr. Thomas Cooper, M.D., at Baylor College of Medicine, recently established a collaboration with Dr. Reed Clark, Ph.D., at the Center for Gene Therapy at Nationwide Children’s Hospital/Ohio State University in Columbus, Ohio, led by Dr. Jerry R. Mendell, M.D.  A major effort of the Center is to develop rAAV vectors for therapeutic approaches for DMD, LGMD, FSHD, and DM1. Once established and optimized in mice, Dr. Gao and her team will work with collaborators to develop rAAV as a therapeutic approach for human trials. This strategy will be developed for DM1, the more common form of DM, but can also be used for DM2 (type 2).

Eric Wang, PhD
Harvard-MIT Health Sciences and Technology, Cambridge, Massachusetts, US

Dr. Wang’s research, “Identification of RNA Processing Changes in the Myotonic Dystrophy Transcriptome,” under the guidance of Dr. Christopher Burge, Ph.D., and Dr. David E. Housman, Ph.D., at Harvard-MIT Division of Health Sciences and Technology (HST), Cambridge, Massachusetts, will help to improve the understanding of DM pathogenesis. Various events associated with the expanded RNA repeat sequences that cause DM have been well established, but there are other hypotheses for what happens during DM pathogenesis. To date there have been no studies globally surveying all the RNA changes in DM, making it challenging for the DM research community to conclude whether it has identified all the major cellular pathways disturbed in DM. Identifying all these changes will provide a research road map, as well as specific readouts that can be used for diagnostics and therapeutic studies. Using a type of high throughput sequencing technology that has been recently developed, Dr. Wang proposes to identify RNA level changes that occur in various mouse models of DM, assess the extent to which current models for DM pathogenesis can explain what is happening in human DM, and develop potential therapeutic interventions using the insights gained from these analyses. The successful completion of these studies will augment the DM community’s understanding of DM pathogenesis, and provide a set of biomarkers that can be used immediately for diagnostics and therapeutic development.

John Cleary, PhD
University of Florida, Gainesville, Florida, US

Working with Dr. Laura Ranum, Dr. Cleary’s research is titled, “An Investigation of the Genetic Mechanisms in Myotonic Dystrophy“ The primary cause of the disease is a mutated version of a gene that contains an excess number of small repetitive sections of DNA. These sections, termed trinucleotide repeats, normally occur in numbers between 5 and 34 but in the mutant version expand upwards to several hundred or even several thousand. As a consequence when transcribed into RNA, the initial step towards making a protein, the repeats, due to their expanded size, soak up cellular proteins that bind repeat-containing RNA creating an RNA gain-of-function effect. Unable to let go of the expanded RNA, these cellular proteins are prevented from accomplishing their regular function and cause a cascade of negative consequences to the cell.

The majority of current research has assumed that certain classes of repeats, due to their location in the gene, are not made into proteins. However recent evidence by the Ranum lab suggests these repeats may actually express a variety of proteins that due to their repetitive nature could have serious cellular consequences. What is perhaps more unexpected is that the repeats make these proteins by essentially taking it upon themselves to start the process – bypassing the cell’s traditional methods by which RNA is made into proteins. These data suggest that in addition to the RNA gain-of-function effects, the expression and accumulation of these unexpected expansion proteins could also contribute to myotonic dystrophy. The focus of Dr. Cleary’s postdoctoral research will be to understand the potential role that these proteins play in disease.

Alexa Dickson, PhD
Colorado State University, Ft. Collins, Colorado, US

Working with Dr. Carol Wilusz, Dr. Dickson’s research is titled, “The Role of mRNA Stability in Myotonic Dystrophy“ Myotonic dystrophy is a genetic disorder caused by an increase of repeats in the DNA. Although the mechanism is unclear, researchers know the increased DNA repeat length causes a defect in CUGBP1, a protein responsible for determining the levels of gene expression in the cell. Without proper control of gene expression, abnormal levels of proteins result, which is thought to cause some of the symptoms in myotonic dystrophy. Dr. Dickson’s proposal examines the role of CUGBP1 in normal cellular function and seeks to determine the defect of the protein in myotonic dystrophy. With this knowledge, researchers may be able to more rationally design therapeutics targeted to improving the quality of life of a myotonic dystrophy patient.

Stacey Wagner, PhD
University of Oregon, Eugene, Oregon, US

Working with principle investigators, Dr. Andrew Berglund and Dr. Michael Haley, Dr. Wagner’s research, „Small Molecule Therapeutics Based on Pentamidine for the Treatment of Myotonic Dystrophy“, aims to modify the existing drug, pentamidine to use as a safe treatment to eliminate the symptoms of myotonic dystrophy. Today, pentamidine carries approval of the U.S. Food and Drug Administration for treating a severe type of pneumonia in people with weakened immune systems, as well as leishmaniasis, sleeping sickness and some yeast infections. Researchers have discovered that levels used successfully in experiments in mice would be toxic in humans so modifications must be made to this compound. Dr. Wagner’s work is focused on finding better pentamidine analogs that are promising as a therapeutic compound for myotonic dystrophy.