The Myotonic Dystrophy Foundation made the following Research Fellowship grants in 2024:

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.

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.

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.

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

The Myotonic Dystrophy Foundation US made the following Research Fellowship grants in 2023:

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 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 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 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 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 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 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.

Auinash Kalsotra, PhD
Baylor College of Medicine, Houston, Texas, US

Working with Dr. Thomas Cooper, Dr. Kalsotra’s research, “Regulatory Mechanisms of CELF Protein in Cardiac Development and Myotonic Dystrophy” aims to identify cellular pathways that are disrupted in myotonic dystrophy type 1 (DM1). In the long term, such an understanding might allow manipulations to correct or circumvent the disease process at the molecular level.

John Lueck, PhD
University of Iowa, Carver College of Medicine, Iowa City, Iowa, US

Working with Dr. Kevin Campbell, Dr. Lueck’s research, “Understanding Muscle Weakness and Wasting in Myotonic Dystrophy”, will investigate the molecular mechanisms underlying muscle weakness and wasting in myotonic dystrophy. The results of this study will not only shed light on the mechanism of muscle disease in myotonic dystrophy type 1 (DM1), but will also help unravel the mysteries of other muscular dystrophies. Ultimately, the goal of this research is to discover new avenues of therapy for myotonic dystrophy.