In partnership, the Myotonic Dystrophy Foundation US and the Myotonic Dystrophy Foundation UK made the following Research Fellowship grants in 2022:
Lily Cisco
University of Rochester Medical Center, Rochester, New York, US
The overall goal of the study is to better understand the mechanism of skeletal muscle weakness and degeneration in myotonic dystrophy (DM) and to determine if repurposing FDA-approved drugs holds therapeutic promise. The study, “identification of altered muscle calcium handling as a potential DM1 therapeutic target” focuses on better understanding what causes the skeletal muscle aspect of the disease, as well as to identify potential druggable targets for the use as therapies to DM skeletal muscle pathology. A strength to this approach is the ability to determine the role of individual DM associated splice event in isolation, and to cross animals to determine their impact in combination. They have found that the combination of only two altered transcripts results in significant muscle weakness, respiratory dysfunction, and shortened lifespan of mice. With therapeutic targets identified, they look to determine if the use of already FDA-approved drugs can be used to treat the mouse models to rescue skeletal muscle and respiratory phenotypes and extend the lifespan of the DM mouse models. They will expand their studies to a more complex DM mouse model to determine if potential treatments are also effective in a model that more closely mimics the disease mechanism. Click here to read more about Lily Cisco and her ongoing work.
Avery Engelbrecht
University of Florida, Gainesville, Florida, US
The goal of the study, the “characterization of a novel BAC transgenic mouse model for DM2”, is to better understand the contribution of both the toxic RNAs and toxic RAN proteins in myotonic dystrophy type 2 (DM2) by characterizing a new mouse model for DM2. The Ranum Lab has had great success with making two different repeat expansion mouse models, one for ALS and a second for SCA8. This study will characterize novel DM2 mice to provide insight into the role of expansion RNAs and RAN proteins in the disease and hopefully to provide a DM2 mouse model that can be used to test therapeutic strategies. The study will leverage the Ranum Lab’s recently published findings that metformin, a known inhibitor of RAN translation, reduces RAN protein levels and improves disease features in a C9orf72 BAC transgenic mouse model of ALS. To explore the potential therapeutic value of metformin in DM2, they will treat their DM2 mice with metformin and examine changes in the molecular and disease features. Taken together, this study will characterize the first BAC transgenic mouse model of DM2, provide insight into the role of expansion RNAs and RAN proteins in DM2, and provide preclinical testing data on a potential therapeutic approach for DM2. Learn more about Avery Engelbrecht and his work.
Jesus Frias
The RNA Institute, University at Albany, New York, US
Myotonic dystrophy (DM) is caused by repeat expansion mutations that produce toxic expanded repeat RNA that leads to a plethora of downstream effects. The research lab has identified possible lead small molecule therapeutics for DM1. Based on previous work from the Berglund Lab, they have developed a new series of small molecules with improved therapeutic efficiency. They have already identified one lead novel compound that rescues hallmarks of DM in cell culture and animal models. In the study, “determining the therapeutic potential and mechanisms of action of novel small molecule therapeutics for DM1”, they will test the therapeutic potential of additional compounds and determine how these compounds work at the molecular level with the aim of developing more effective therapeutics for the disease and ultimately in addressing the need for treatments for DM. Click here to read more about Jesus Frias and his prior research.
Christina Heil, PhD
University of Rochester Medical Center, Rochester, New York, US
Diagnostic testing for myotonic dystrophy (DM) is needed to provide genetic counseling and prognosis for patients. Current standards have limitations to determining the accurate size of the repeat expansion, and they can fail to detect variant repeats that usually cause milder symptoms. Extremely long repeat expansions found in tissues like skeletal muscle are particularly difficult to analyze. Long-read DNA sequencing is a relatively new and fast advancing technique, that has proven useful in characterizing long repeat expansions but has not yet been widely employed. It is able to not only determine accurate repeat size but also gives information about the full repeat sequence, revealing possible repeat interruptions that might stabilize the repeat expansion. Furthermore, long-read DNA sequencing depicts the heterogeneity of repeat sizes found in a person’s blood sample and can be used to assess repeat instability. The study, “genetic characterization of DM1 models”, plans to use this new technique to study age-dependent repeat instability in DM1 mouse models. They will also study the effects of antisense oligonucleotide treatment. Results will further shed light onto the potential impact of repeat instability on disease progression. Optimized protocols established in this study will help long-read DNA sequencing become a rapid and powerful tool for research and clinical care, aiding better characterization of this repeat expansion disorder and better genetic counseling and prognosis for patients. Learn more about Dr. Heil and her work.
Preeti Kumari, PhD
Massachusetts General Hospital, Boston, Massachusetts, US
The goal of the study, “molecular biomarkers of myotonic dystrophy in cerebrospinal fluid”, is to use cerebrospinal fluid (CSF) samples from myotonic dystrophy (DM) patients to identify markers of brain involvement that can be used to detect early changes in the progression of DM and determine whether new treatments are working. The rationale is that small particles called extracellular vesicles (EVs) are released from many different cell types into the urine, blood, and CSF. EVs contain molecules called extracellular RNAs (exRNAs) that can serve as biomarkers of cancers and other disease states. Their research group was the first to demonstrate that EVs in urine also contain a certain type of exRNA that can serve as specific biomarkers of DM and other muscular dystrophies. Recently, they also have found these exRNAs in the CSF. However, to date relatively little is known about the extent of the changes in exRNA that occur in DM patients as compared to healthy individuals, including the relationship of exRNA markers to the underlying disease state or rate of progression. CSF exRNAs are a rich and renewable biomarker source that has the potential to enable convenient non-invasive monitoring of disease activity and determine at an early stage or whether a new drug is having its intended effect during the course of treatment so that the dose may be adjusted upward or downward as needed. This would speed the evaluation of drug efficacy and decrease the time it takes to have a new drug available for patient use. Learn more about Dr. Kumari and her work.
Larissa Nitschke, PhD
Baylor College of Medicine, Houston, Texas, US
Nitschke’s broad research interest is to investigate the regulation of genes involved in human diseases, with a hope that a better understanding of their regulatory mechanisms will help uncover disease risk factors and guide the way to the development of novel treatment options and therapeutic approaches. Her study “the compensatory mechanism of MBNL proteins and its importance in myotonic dystrophy type 1 (DM1) disease” aims to 1) determine the molecular details by which the MBNL2 protein is increased upon loss of MBNL1, 2) investigate the extent to which the compensatory mechanism counteracts DM1 disease and, 3) test if the mechanism can be extrapolated to improve DM1 symptoms. The study thereby lays the foundation for future studies investigating if the compensatory mechanism can be modulated for therapeutic purposes. Learn more about Dr. Nitschke's work.
Zoe Scherzer
University of Florida, Gainesville, Florida, US
Excessive sleepiness prevents myotonic dystrophy (DM) patients from being able to hold down jobs, function normally in social situations, and participate in normal relationships. Though sleep problems seen in people with DM are well-documented and established, causes underlying this set of symptoms remain to be discovered. Using a top-down approach to study causes of DM-associated sleep problems, this study, “investigating the contribution of circadian disruption in DM-associated sleep disorders”, will classify the exact profile of these issues starting at a large scale (whole body). They will then investigate individual components within the body (events happening within body cells). This research aims to answer key questions to provide groundwork for future therapeutic interventions. Learn more about Zoe Scherzer's work.
Xiaomeng Xing
University of Nottingham, England, UK
Xing’s study, the “analysis of DMPK expansion transcript degradation and MBNL–RNA binding kinetics in myotonic dystrophy type 1 (DM1)” has three main aims. The first aim is to work out how cells degrade the mutant expRNAs with a view to making this a focus for future therapeutic approaches. DM is caused by additional DNA sequences which are copied into RNA and then get stuck in the nuclei of patient’s cells. This extra RNA sequences (expansion RNA or expRNA) interact with proteins called MBNL1 and MBNL2 and it is widely considered that this interaction is one of the most important events causing the condition. To understand this, the study will screen multiple enzymes to work out which ones are the most important for degrading the expRNA in patient’s cells. The second aim is to develop a reliable and accurate method to count mutant DMPK transcripts by using new technology. This could have great benefits for many different projects and approaches being developed to treat DM, as it will provide a biomarker (readout) for the primary cause of the condition, the mutant expRNA. Finally, the study will attempt to decode the complex link between MBNL–RNA binding and MBNL function using a new technique called KIN-CLIP, to measure the binding and dissociation kinetics of RNA– MBNL interactions. Learn more about Xiaomeng Xing's work.