The Myotonic Dystrophy Foundation made the following Research Fellowship grants in 2024:

Betty Bekele 
Emory University, Atlanta, Georgia, US

In people with Myotonic Dystrophy Type 1 (DM1), one of the most common non-muscle symptoms is disordered sleep such as trouble falling asleep at night, sleeping for extended hours during the day, and sleep apnea (obstruction of breathing during sleep). Moreover, DM1 patients face unique challenges related to anesthesia including increased sensitivity to drugs, delayed recovery, and respiratory complications that can be fatal. This study “Altered Inhibitory Neurotransmission in Mouse Models of Myotonic Dystrophy Type 1 (DM1)” delves into the impact of DM1 on Gamma-Aminobutyric Acid (GABA), a crucial brain chemical for sleep and anesthesia sedation. GABA controls how active or “excited” our brain cells (neurons) are through special channels called GABAA receptors that are found on the surface of neurons. These channels have different parts called subunits which are like puzzle pieces. The combination of these subunits can change as we grow up. Moreover, each subunit can have different versions (isoforms) because of a process called "alternative splicing," which is like mixing and matching puzzle pieces to create unique proteins that can perform different functions. In the adult brain, most GABAA receptors are made up of three parts: alpha1, beta1, and gamma2. The gamma2 subunit is essential for the function of most anesthetic drugs and has two splice variants: a longer one called "gamma2L" and a shorter one called "gamma2S." The longer isoform gamma2L is found at specific neuronal connections (synapses), while the shorter isoform gamma2S is found in places outside of the synapse (extrasynaptic sites). In people with DM1, the short variant gamma2S is found at higher levels than the long variant gamma2L Using mouse models of DM1, the study records neuronal electrical activity to understand how this isoform shift influences GABA and GABAA receptor-targeting drugs. By examining how drugs affect neuronal activity, they will gain insights into DM1's impact on the brain and can test potential therapies. One such drug under consideration is flumazenil, aimed at reversing GABA's effects to alleviate sleep issues and counter anesthesia effects. This approach not only enhances the understanding of DM1's neurological aspects but also offers a pathway for testing promising treatments to improve patient outcomes.

Sakura Hamazaki
University of Rochester, New York, US

DM1 affects various organs, presenting symptoms like myotonia, weakness, and muscle wasting. Despite being one of the most debilitating aspects of DM1, the direct cause of muscle weakness and wasting is yet to be understood. This has been particularly challenging due to the widespread effect of the genetic lesion responsible for DM1; however, without the understanding of these specific targets, generating therapeutics for patients is difficult. Recent research points to altered ion channels crucial for muscle contraction as contributors to DM1-related weakness. To explore this further, they have developed mouse models expressing these channels, pinpointing one that, when forced into DM1-like conditions, leads to reduced lifespan and muscle/respiratory issues. This discovery establishes a potential therapeutic target. The next step involves correcting this channel's function, assessing its impact on overall muscle health using established mouse models to validate therapeutic benefits. Unlike conventional drug testing, this method minimizes concerns about unintended effects. Successfully completing this study “Impact of calcium entry through Cav1.1 in myotonic dystrophy myopathy” will definitively identify ion channels as new therapeutic targets for DM1 myopathy, bolstering confidence in developing novel treatments or repurposing existing FDA-approved drugs.

Alexandra L. Marrero Quinones
Virginia Commonwealth University, Richmond, Virginia, US

DM1 results from a DNA repetition (CTG repeat) in the DMPK gene, expanding across generations. In general, CDM children are born to DM1 mothers with high repeat loads who experience disease early in life. However, some children born to mildly affected mothers unexpectedly develop severe symptoms from a rapid repeat expansion. The cause of this rapid expansion is unclear, but it's suspected to involve genes repairing damaged DNA. To address this question, blood samples from 45 CDM patients and parents were collected. In preliminary work with 10 families with rapid expansion, they found damaging variations in the DNA repair gene MSH3. These variations, inherited with the DM1-causing gene, impair global DNA repair in cells. This suggests a link between MSH3 variants and DM1 repeat instability, contributing to the rapid genetic changes observed with maternal inheritance. In the “Evaluation of MSH3 as a Genetic Modifier of Trinucleotide Repeat Instability in Myotonic Dystrophy” project it is their objective to further evaluate the role in DM1 repeat instability of these MSH3 variants and other inherited DNA repair variants identified through DNA sequencing of families with rapid repeat expansions. This may identify new potential therapeutic targets while providing insight into the role of DNA repair mechanisms in DM1 CTG repeat instability and the progression of disease.

Cameron Niazi
University of Florida, Gainesville, Florida, US

DM1 is a genetic disorder caused by a gene that, when broken, produces a toxic RNA that makes the patients’ cells sick. The faulty gene is like a broken faucet pumping out dirty water (RNA) that contaminates the cell that it empties into. Traditional treatments focus on eliminating or neutralizing the toxic RNA, but the underlying issue persists—the broken gene keeps producing harmful RNA. Advances in CRISPR/Cas gene editing offer a new approach to fix the gene by using "molecular scissors" to cut and repair the patient's DNA, effectively fixing the broken faucet. However, safety concerns surround using CRISPR/Cas in humans, as the "molecular scissors" may inadvertently cut the wrong gene, leading to severe consequences like cancer or other serious adverse events. The project “Leveraging CRISPR/Cas-based Epigenetic Modifications for the Treatment of Myotonic Dystrophy Type 1” represents a modified CRISPR/Cas based “epigenetic silencing” approach that has fewer safety risks compared to most gene editing strategies being pursued for DM1. Epigenetics refers to factors that control how genes are turned on and off. Rather than using “molecular scissors” to go in and cut the problematic DNA. Instead of cutting the problematic DNA, this approach removes CRISPR's "molecular scissors" blades, turning the gene off without physically altering it. Using this approach, we can shut off the faucet and stop the toxic RNA from being pumped into the cell without the risks associated with cutting the gene. CRISPR/Cas based targeted epigenetic therapeutics to turn genes “on” and “off” have attracted significant attention and funding in biotech and pharmaceutical industries. However little work has been done to adapt this technology for DM1. The proposed work will be a first step to bringing this promising new technology to the DM1 community and will serve as a valuable test of its overall feasibility as a therapeutic approach. Click here to read more about Mr. Niazi