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 Participating centers would share existing, partly unpublished natural history data, refine suitable outcome measures, provide for identification of patient populations and qualify trial sites.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.
- Laurie Gutmann, M.D., University of Iowa, 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.