The Myotonic Dystrophy Foundation (MDF) supports scientific investigations to enhance the quality of life of people living with myotonic dystrophy and advance research focused on finding treatments and a cure for this disease.
Grantwriting Training for Researchers
MDF hosted a grant writing training at the 2014 MDF Annual Conference, presented by Dr. John Porter, PhD, former Program Director at NINDS/NIH. Click here to view the PowerPoint presentation from that training and access best-in-class grantwriting tips.
2017 Grant Recipients
In partnership with MDF, the Wyck Foundation made the following Fellowship grants in 2017:
Anwesha Banerjee, Ph.D.
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, Ph.D.
University of Florida
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.
2016 Grant Recipients
In partnership with the Wyck Foundation, London, UK, MDF is pleased to announce the following 2016-2017 Grant Recipients:
RESEARCH & GRANT AWARDS
PicnicHealth Registry Project
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.
Nicholas E. Johnson, MD
University of Utah, U.S.
Prevalence of Myotonic Dystrophy
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 the Wyck Foundation and MDF 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.
Alexandra Breukel, PhD
European Neuromuscular Centre, Netherlands
Workshop Support - Myotonic Dystrophy: Developing a European Consortium for Care and Therapy
This Wyck Foundation and MDF-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 U.S.
Cathleen Lutz, PhD
The Jackson Laboratory, U.S.
Building a Better Mouse
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.
Thurman Wheeler, MD
Massachusetts General Hospital, U.S.
Extracellular RNA as Biomarkers of Myotonic Dystrophy
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.
Michael Sheldon, PhD
RUCDR Infinite Biologics, Rutgers University, U.S.
DM Cell Line Library
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, U.S.
- John Day, M.D., Ph.D., Stanford University, U.S.
- Nicholas Johnson, M.D., University of Utah, U.S.
- John Kissel, M.D., Ohio State University, U.S.
- Jeffrey Statland, M.D., University of Kansas Medical Center, U.S.
- S.H. Subramony, M.D., University of Florida, U.S.
Hanns Lochmüller, MD
Newcastle University, U.K.
PHENO-DM1- Myotonic Dystrophy type 1 (DM1) deep phenotyping to improve delivery of personalised medicine and assist in the planning, design and recruitment of clinical trials
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 the Wyck Foundation, in partnership with MDF, 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.
Donovan Lott, PhD
University of Florida, U.S.
Development of Magnetic Resonance Imaging as an Endpoint in Myotonic Dystrophy Type 1
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.
Ian DeVolder, PhD
University of Iowa, U.S.
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
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, U.S.
Evaluation of Functional Connectivity as a Brain Biomarker in Congenital Myotonic Dystrophy
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
A 14-Year Longitudinal Study of Cognition and Central Nervous System Involvement in Adult and Late-Onset Phenotypes of Myotonic Dystrophy Type 1
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 DystrophyType 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, U.S.
Mechanisms of Skeletal Muscle Wasting Caused by Expanded CUG Repeat RNA
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
A New Approach of Pathomolecular Mechanisms in Myotonic Dystrophy Insulin Resistance by Nutrigenomics
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, U.S.
Myotonic Dystrophy Type 2 - Mouse Models, Pathomechanism and Therapy
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.
MDF is also pleased to announce the following 2016 grant program:
Clinical Coordinators Recognition Program
MDF is funding a professional development and recognition program for clinical care coordinators and physical therapists at DMCRN and clinical trial sites. The goal is to create a coordinators' network and program through conference meetings, communications, education and training events, and networking calls.
2015 Grant Recipients
In partnership with the Wyck Foundation, London, UK, MDF made the following Fellowship grants in 2015:
Dr. Ranjan Batra, Ph.D.
University of California, San Diego
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, Ph.D.
The Scripps Research Institute of Florida
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, Ph.D.
University of Oregon
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.
In partnership with the Wyck Foundation, MDF made the following additional awards in 2015:
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.
2014 Grant Recipients
Dr. Jintang Du
The Scripps Research Institute
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.
Dr. Yao Yao
The Rockefeller University
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.
2013 Grant Recipients
Dr. Ayal Hendel, Ph.D.
Stanford School of Medicine
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.
Dr. Suzanne Rzuczek, Ph.D.
The Scripps Research Institute, Florida
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.
2012 Grant Recipients
Micah Bodner, Ph.D.
University of Oregon, Eugene, Oregon, USA
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, M.D.
University of Rochester Medical Center, Rochester, New York, USA
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, Ph.D.
Baylor College of Medicine, Houston, Texas, USA
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, Ph.D.
Harvard-MIT Health Sciences and Technology, Cambridge, Massachusetts, USA
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.
2011 Grant Recipients
John Cleary, Ph.D.
University of Florida in Gainesville, Florida, USA
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, Ph.D.
Colorado State University in Ft. Collins, Colorado, USA
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.
2010 Grant Recipients
Stacey Wagner, Ph.D.
University of Oregon in Eugene, Oregon, USA
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.
2009 Grant Recipients
Auinash Kalsotra, Ph.D.
Baylor College of Medicine in Houston, Texas, USA
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, Ph.D.
University of Iowa, Carver College of Medicine, Iowa City, Iowa, USA
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.