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.