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

2023 MDF Early Career Researchers

Dylan Farnsworth, PhD
Senior Research Scientist
The RNA Institute, University of Albany, New York, US

Myotonic dystrophy (DM) disrupts gene expression across almost all organ systems. Within these organs, there are many distinct cell types formed by the expression of genes that are specific to a cell’s function. For example, muscle, bone, and intestinal cells all express a different set of genes, which will all be affected differently by the DM repeat expansion. In order to understand how the DM mutations cause symptoms, researchers must first understand which cells express the genes that lead to DM, and second, how the expression of all genes required by these cells is affected in DM. One of the best ways to address this issue is using zebrafish, a vertebrate model organism with recreated genetic mutants that cause DM in humans. This can simultaneously allow researchers to analyze the gene expression patterns of many cell-types across the entire animal. In the project, “Connecting cell-type specific gene-expression patterns in DM-model zebrafish to sleep and circadian disruptions and enhanced therapeutic development”, Dr. Farnsworth and colleagues will link DM-causing genes with cell-types, and cell-types with symptoms. They will use this knowledge to test drugs on zebrafish that can rescue these cell-type specific gene expression patterns and alleviate DM symptoms. Specifically, zebrafish with DM-associated mutations have defects in gastrointestinal (GI) function and regulation of circadian genes that mirror the digestive symptoms and sleep disruption reported by DM patients. Since drug-testing in zebrafish is very rapid and accessible, they will test currently available drugs for their ability to alleviate these DM symptoms. Click here to read more about Dr. Dylan Farnsworth.

Matteo Garibaldi, MD, PhD
Assistant Professor
Sapienza University of Rome, Italy

Muscle weakness in myotonic dystrophy type 1 (DM1) is the consequence of progressive fat replacement of muscles. Muscle MRI studies can reveal if muscles are spared or affected. In many muscle diseases fat replacement is preceded by hyperintense signal in specific MRI sequences (STIR), representing a signature of disease ‘activity’. Consequently, muscle MRI can reveal unaffected muscles, actively affected but still unreplaced muscles, and affected muscles. Some muscles in DM1 are early affected while others remain spared in the course of the disease. This phenomenon leads to a disease-specific pattern of muscle involvement detectable by muscle MRI. Dr. Garibaldi and colleagues recently reported muscle MRI data from a large cohort of DM1 patients showing that DM1 muscle involvement is characterized by progressive fat replacement that is preceded by a period of STIR positivity. In the project, “TranSTIRomics for DM1 - Where the disease begins: a muscle MRI-based transcriptome study in myotonic dystrophy type 1”, Dr. Garibaldi and colleagues aim to understand the biological processes occurring in STIR+ muscles by histopathological and transcriptome (gene expression) analyses. This study will reveal novel insights into pathophysiological mechanisms of muscle weakness in DM1. This will allow a better understanding of what happens when the disease begins and provide novel biomarkers and potential therapeutical targets for the earliest stages of disease. The results will be important for timing the start of treatments, allowing for the identification and treatment of patients in the earliest stages of disease, when the disease switches from a quiescence state to the active-pre-symptomatic phase, anticipating fat replacement and preventing muscle weakness. Click here to ready more about Dr. Matteo Garibaldi.

Melissa Hale, PhD
Assistant Professor
Virginia Commonwealth University, Richmond, Virginia, US

Children with congenital myotonic dystrophy (CDM) present with a unique set of symptoms compared to adults with myotonic dystrophy type 1 (DM1). Unlike in adults, where muscle symptoms decline with age, CDM muscle symptoms often improve in early childhood. How this change occurs is unknown. To date, most research on this has been defined in the context of adult-onset DM1. However, with the distinct presentation of CDM, it is Dr. Hale’s expectation that other cellular processes may occur in CDM children. To address this hypothesis, she recently performed large-scale RNA sequencing to discover differences in the muscle of CDM children across childhood development using muscle biopsies from 34 CDM individuals from 2 weeks – 16 years of age. To date, this is largest dataset of its kind focused exclusively on CDM. This analysis revealed that markers of muscle cell dysfunction in CDM universally improve in early childhood, often to the level of unaffected children, post-severe disease onset at birth. This matches the period where muscle function improves in patients. The goal of her project, “Defining contribution of muscle stem cell activation to dynamic congenital myotonic dystrophy transcriptome”, is to investigate the contribution of a unique population of cells in skeletal muscle, called muscle stem cells (MuSCs), to the molecular signatures observed. MuSCs represent a unique population of cells embedded in all muscles of the body that can regenerate and repair muscle. An understanding of their activity in CDM across childhood development will not only provide a better understanding of the disease but may illuminate potential new therapeutic targets for the most severely affected patients. Click here to read more about Dr. Melissa Hale.