In partnership, the Myotonic Dystrophy Foundation US and the Myotonic Dystrophy Foundation UK made the following grants in 2016:
“PicnicHealth Registry Project”
PI: Noga Leviner
PicnicHealth, San Francisco, California, US
This is a proposal to design and execute on a pilot project to 1) collect medical records and 2) structure medical record data for a cohort of 100–200 myotonic dystrophy patients using PicnicHealth’s patient-centered medical records collection and management platform. This pilot study will determine whether the approach is a feasible one for constructing DM patient natural histories.
“Prevalence of Myotonic Dystrophy”
PI: Nicholas E. Johnson, MD
University of Utah, US
This project is a Population-Based Prevalence Study in Myotonic Dystrophy Type-1 and Type-2. The prevalence of myotonic dystrophy type 1 and type 2 are unknown. This is at least partly due to the wide variation in the age of onset and individuals with the disease who have not been diagnosed; both of which would not be accounted for in a traditional prevalence study. To address this issue MDF US and MDF UK issued a two-phase RFA. The phase I RFA was designed to develop an assay that could be used in a population-based screen. The phase II RFA provides funds sufficient to implement a screen in a group representative of the general population, for example, via newborn bloodspots or via banked blood from other ongoing studies as appropriate. In phase I, Dr. Johnson was awarded a grant to develop and validate a cost-effective screening methodology capable of estimating the prevalence of DM1 and DM2 mutations and pre-mutations in the general US population. In phase II, Dr. Johnson’s application received the grant award to use a population sample of de-identified newborn blood spots to determine carriers of DM mutations and pre-mutations. This will provide the first-ever large-scale population-based prevalence study of myotonic dystrophy types 1 and 2.
“Workshop Support - Myotonic Dystrophy: Developing a European Consortium for Care and Therapy”
PI: Alexandra Breukel, PhD
European Neuromuscular Centre, Netherlands
This Myotonic Dystrophy Foundation US and the Myotonic Dystrophy Foundation UK-supported workshop was focused on establishing a mechanism for international collaboration between expert centers in Europe in order to ensure better coordination for DM clinical trials. Participating centers would share existing, partly unpublished natural history data, refine suitable outcome measures, provide for identification of patient populations and qualify trial sites. Moreover, the establishment of networking of the existing knowledge, infrastructure and personnel would facilitate appropriate inclusion and communication of patients and patient organizations, the interaction with commercial as well as academic trial sponsors and the involvement of regulators and payers along the translational pathway. Foundation interests in this effort include establishing strong partnerships between the new European consortium and the existing Myotonic Dystrophy Clinical Research Network (DMCRN) in the US.
“Building a Better Mouse”
PI: Cathleen Lutz, PhD
The Jackson Laboratory, US
This project will support the development of a new BAC transgenic mouse model of myotonic dystrophy type 1 (DM1) at the Jackson Laboratory (JAX). This will be accomplished by creating a BAC transgenic with a large CTG repeat and a wildtype control. The funding provided will be used to create the model with some baseline clinical observations of weight, survival and overt phenotypes. Using a BAC approach to express the expanded repeat in all tissues will increase the probability of emulating the multi-systemic nature of DM by showing defects in the CNS, heart and other organ systems, as well as muscle. In addition to the need for new models to better understand disease mechanisms, industry views a better DM1 mouse model as essential to its therapeutic development efforts.
“Extracellular RNA as Biomarkers of Myotonic Dystrophy”
PI: Thurman Wheeler, MD
Massachusetts General Hospital, US
A new drug for treatment of DM1 is being tested in clinical trials. Monitoring drug effects currently requires that patients undergo multiple muscle biopsies, a procedure that is invasive, painful and, in pediatric patients, requires general anesthesia. The goal of this project is to develop biomarkers in human urine or blood that:
Will reduce or eliminate the need for muscle biopsies to determine whether treatments are working
Can be measured multiple times as needed during the trial
Enable inclusion of children with DM1 in upcoming trials
The approach will be applicable to many different treatment strategies for both DM1 and DM2.
“DM Cell Line Library”
PI: Michael Sheldon, PhD
RUCDR Infinite Biologics, Rutgers University, US
This grant award is intended to support the development of eight new DM iPSC lines at RUCDR Infinite Biologics for distribution to qualified investigators at academic institutions and biotech/pharmaceutical companies. Numerous companies seeking to develop therapies for DM have reported that they are having difficulty obtaining well-documented cell lines for DM1 and DM2. High-throughput screening programs for small molecule development in other neuromuscular diseases have found results that differ based upon the cell type used in the screen. By making human iPSC cells derived from fibroblasts of patients with expanded repeats (>400) available, researchers and drug developers will be able to derive cell types (e.g. neurons, myocytes, cardiomyocytes) appropriate to their needs. There will be no licensing fees or reach-through on intellectual property, ensuring that commercial development efforts are unhindered.
“Myotonic Dystrophy Clinical Research Network (DMCRN) Site Grants: Multicenter Study of Natural History and Genetic Modifiers in Myotonic Dystrophy Type 1”
During the last project period, the DMCRN completed its first project, a study of natural history and RNA biomarkers in 100 patients with DM1. The DMCRN subsequently expanded the enrollment and expects to have one year follow up data on 100 subjects by the first quarter of 2017. The results of the DMCRN collaboration abundantly confirmed that RNA splicing biomarkers are tightly linked to the disease process and reliable for monitoring disease activity. The methods and data will be taken forward to the FDA for formal qualification of splicing biomarkers as drug development tools for DM1. The DMCRN is now pursuing parallel work for DM2.
The DMCRN will undertake an ambitious 8-site study of disease progression and genetic modifiers of DM1. The proposed study will use unrestrictive entry criteria, ensuring that any subject with DM1 is included. To meet the increased recruitment demands, the study involves new sites (University of Utah, Salt Lake City and Houston Methodist Neuroscience Institute, Houston, TX) and concise study visits (2-3 hours) that do not include invasive procedures. It is expected that this will drive strong enrollment and allow participation from segments of the community who previously may have felt disenfranchised. As compared to the current study, it examines a larger number of patients (n = 500) over a longer time period (2 years). The outcome measures are a subset of those used in previous studies, selecting those with best performance characteristics.
Six DMCRN site awards have been issued (two DMCRN sites - the National Institutes of Health: Ami Mankodi, M.D., and the University of Rochester, Drs. Richard Moxley III, M.D, and Charles Thornton, M.D., - have separate funding sources):
Tetsuo Ashizawa, M.D., Houston Methodist Neuroscience Institute, US
John Day, M.D., Ph.D., Stanford University, US
Nicholas Johnson, M.D., University of Utah, US
John Kissel, M.D., Ohio State University, US
Jeffrey Statland, M.D., University of Kansas Medical Center, US
S.H. Subramony, M.D., University of Florida, US
Laurie Gutmann, M.D., University of Iowa, US
“PHENO-DM1- Myotonic Dystrophy type 1 (DM1) deep phenotyping to improve delivery of personalized medicine and assist in the planning, design and recruitment of clinical trials”
PI: Hanns Lochmüller, MD
Newcastle University, UK
Myotonic dystrophy type 1 (DM1) is the most common adult-onset muscular dystrophy. The multisystemic phenotype may be highly variable between patients and therefore the selection of appropriate endpoints for therapeutic trials is of great importance for trial readiness. Newcastle University and University College London are working together to deep-phenotype 200-400 DM1 adult patients in the UK and investigate potential biomarkers and skeletal muscle MRI over 9-12 months. The team is currently funded through a UK National Institute for Health Research grant. The on-going study represents an opportunity to leverage the existing funding and data in order to obtain detailed, long-term (24 month) phenotypic data from a large DM1 cohort. Funding from MDF UK, in partnership with MDF US, will extend the study for an additional 18 months, thereby providing extensive natural history data that will be invaluable in design of clinical trials in DM1.
“Development of Magnetic Resonance Imaging as an Endpoint in Myotonic Dystrophy Type 1”
PI: Donovan Lott, PhD
University of Florida, US
Magnetic Resonance Imaging (MRI) has been very useful in examining the muscles of people with different diseases, and it should be important for assessment of people with myotonic dystrophy type 1 (DM1). The goal of this study is to develop MRI of the legs and arms for people with DM1 so that MRI can be used as an endpoint in clinical trials. Specifically, Dr. Lott and team will use MRI to measure different ways the DM1 disease affects muscles and will examine how those measures relate to walking, balance, falls, strength, and arm function.