Professional Session Abstracts - 2022 MDF Annual Conference

MDF invites you to attend the 2022 MDF Annual Conference - sometimes called the “family reunion” - from Friday, September 9th through Saturday, September 10th, 2022, at Paradise Point in San Diego, CA. For those arriving early, we welcome you to join us for a Thursday evening reception. For those unable to attend in-person, we welcome you to join us virtually!

Professional Session Abstracts

This track was designed with expert guidance from members of MDF’s Scientific Advisory Committee. Attendees must have a professional registration. Read the presentation abstracts for each Professional Track Presentation Below.

Friday, September 9th

9:00am | Endurance exercise leads to beneficial molecular and physiological effects in the HSALR mouse model of myotonic dystrophy type 1

Presented by Thomas A. Cooper, MD - Baylor College of Medicine

Abstract Introduction: Myotonic dystrophy type 1 (DM1) is a multisystemic disease caused by expansion of a CTG repeat in the 3' UTR of the Dystrophia Myotonica-Protein Kinase (DMPK) gene. While multiple organs are affected, more than half of mortality is due to muscle wasting. Methods: It is unclear whether endurance exercise provides beneficial effects in DM1. Here, we show that a 10-week treadmill endurance exercise program leads to beneficial effects in the HSA LR mouse model of DM1. Results: Animals that performed treadmill training displayed reduced CUGexp RNA levels, improved splicing abnormalities, an increase in skeletal muscle weight and improved endurance capacity. Discussion: These results indicate that endurance exercise does not have adverse effects in HSALR animals and contributes to beneficial molecular and physiological outcomes. From: Sharp, L., Cox, D. C. & Cooper, T. A. Endurance exercise leads to beneficial molecular and physiological effects in a mouse model of myotonic dystrophy type 1. Muscle & Nerve 60, 779–789 (2019).

9:25am | Exercise and nutritional strategies for myotonic dystrophy

Presented by Mark Tarnopolsky, MD, PhD, FRCP(C) – McMaster University

Objective:  To describe the research and practical applications of exercise and nutritional interventions for patients with myotonic MD using human data and experience. Relevance to DM field: Exercise therapy is the only known safe and practical method to improve functional capacity and maintain/attenuate the rate of motor decline in DM1/2 patients.  Identification and treatment of common nutritional deficiencies can prevent serious medical complications and/or compliment other therapeutic approaches. Methods: I will present observational, retrospective and prospective clinical trial data from our clinic (~ 500 DM1 patients and ~ 80 DM2 patients) to identify nutrient deficiencies, exercise therapy and nutraceutical interventions to improve functional capacity and quality of life. Results: A high proportion of MD patients have nutrient deficiencies (vitamins D, B12, E, protein) that can compromise optimal muscle growth and health.  Creatine monohydrate in non-exercising DM1 patients did not appear to provide clinical benefits but limited data in DM2 suggests some benefits.  A very high proportion of DM1 patients have high body fat and low muscle mass (sarcopenic obesity).  DM1 patients who exercise regularly have higher quantitative muscle strength vs sedentary patients.  Three months of cycle exercise (3 X/week X 35 minutes) improved muscle mass, aerobic fitness, and functional tasks in DM1 patients. Conclusions/Future Work: We will be studying (Jan 2023, CIHR grant) the interactive and independent effects of combined endurance + resistance exercise and a DM targeted multi-ingredient nutritional supplement to see if we can improve, fitness, strength and reduce sarcopenic obesity.

10:00am | Strength training effectively alleviates skeletal muscle impairments in myotonic dystrophy type 1

Presented by Elise Duchesne, PhD - Université du Québec à Chicoutimi

Objective/relevance: Progressive muscle weakness and atrophy are cardinal features of myotonic dystrophy type 1 (DM1). The aim of this project was to evaluate the effects of a strength training program over time on lower limb maximal isometric muscle strength (MIMS), vastus lateralis fiber size and function in men with DM1. Methods/procedure: Eleven men with DM1 underwent a 12-week lower limb strength training program, consisting of twice-a-week exercises involving 3 series of 6-8 repetition maximum (RM) of five lower limb training exercises. For each participant MIMS, 30-second sit-to-stand, comfortable and maximal 10-m walk test (10 mwt) were evaluated at baseline, 6 and 12 weeks, and at 6 and 9 months. The one-repetition maximum (1-RM) strength evaluation method of the training exercises was completed at baseline, 6 and 12 weeks. Muscle biopsies were taken in the vastus lateralis at baseline and 12 weeks to evaluate muscle fiber typing and size (including atrophy/hypertrophy factors). Results: Performance in strength and functional tests all significantly improved by week 12. MIMS of the knee extensors decreased by month 9, while improved walking speed and 30-second sit-to-stand performance were maintained. On average, there were no significant changes in fiber typing or size after training. Individualized analysis showed that abnormal hypertrophy factor at baseline could explain the different changes in muscle size among participants. Conclusions/Future work: Strength training induces MIMS and lasting functional gains in DM1. The underlying mechanisms remain to be explored and an individualized approach seems important to better understand this positive response to exercise in DM1.

10:15am | Analysis of individual transcriptomic response to strength training for myotonic dystrophy type 1 patients reveals rescue at the molecular level

Presented by Andrew Berglund, PhD – RNA Institute & University of Albany

Objective: To understand the impact of strength training at the molecular level for men with myotonic dystrophy type 1 (DM1). Muscle biopsies from the vastus lateralis (quadricep) were taken from nine males with DM1 before and after a 12-week strength training program and RNA-sequencing (RNA-seq) was performed on RNA isolated from these samples. Six control males that did not undergo the strength training program provided quadricep muscle samples and RNA-seq was done on RNA from these samples for comparison to unaffected individuals. Methodology: Differential gene expression and alternative splicing analysis were performed on the RNA-seq data to quantify changes at the transcriptome level after training. These molecular outcomes were correlated with the one-repetition maximum strength evaluation method of the training exercises (leg extension, leg press, hip abduction, and squat). Results: Strength training improvements at the level of splicing were observed to be similar among most individuals, although which events were rescued varied considerably between individuals.  Improvements at the level of gene expression were also highly varied between individuals with the percentage of differentially expressed genes rescued after training strongly correlated with clinical strength improvements. Evaluating transcriptome changes individually revealed responses to the strength training program that may otherwise be overlooked when analyzed as a whole group, due to disease heterogeneity and individual differences in response to exercise. Conclusions: Our analyses indicate that splicing and gene expression changes are likely associated with clinical outcomes for DM1 patients who exercise, but that these changes are often specific to the individual and should be analyzed accordingly.

10:40am | Considerations & open discussions of exercise impact on clinical trials and everyday health

Presented by Tina Duong, MPT, PhD – Stanford University

Dr. Duong will present and facilitate discussion of two key questions. 1. Increase exercise may impact outcomes in clinical trials based on exercise literature, research, etc.; how, then, should clinicians promote physical activity while controlling for its effects in studies? 2. How can clinicians and researchers measure and/or control for physical activity in study and trial participants and/or develop appropriate exclusion criteria?

12:00pm | Generation of Bi-channelopathy DM Mice and Drug Repurposing

Presented by John Lueck, PhD – University of Rochester

12:30pm | Screening and synthesis approaches to small molecule discovery reveals new classes of compounds that reduce the toxic RNAs causing myotonic dystrophy

Presented by Andrew Berglund, PhD – RNA Institute & University of Albany

Objective: Reducing the levels of the toxic CUG/ CCUG RNAs through different approaches has proven effective in models of myotonic dystrophy type 1 (DM1) and type 2 (DM2). Our goal is to identify new small molecules that rescue the toxicity by selectively reducing the CUG/CCUG RNAs or upregulating RNA binding proteins (RBPs). This approach employs engineered screening cell lines, DM patient-derived cells and DM1 mice to identify and evaluate potential DM therapeutics. Methodology: Small molecule libraries and novel synthesized small molecules are tested in our DM1 HeLa cell model that provides a rapid readout for selective reduction of the expanded CUG RNA [1]. Lead candidates that reduce the expanded RNA are evaluated in DM1&2 patient-derived fibroblasts, DM1 myotubes, and DM1 HSALR mice. Biochemical, cellular, splicing and RNAseq assays are used to study and refine the mechanism of action of promising lead candidates. Results: Our small molecule studies have identified three classes of compounds that reduce toxic RNA levels: Class 1 contains novel synthetic molecules and works through down regulation of toxic RNA and upregulation of RBPs; Class 2 contains FDA approved molecules; and Class 3 contains natural products. All classes show robust splicing rescue in DM1, DM2 cell models and DM1-HSALR mice. Our lead candidate, a natural product analog, has an excellent safety profile, significantly reduces toxic CUG RNA and rescues splicing across DM1 and DM2 cells and DM1 mice. Conclusions: Our screening and synthesis approaches have identified several lead candidates that provide the foundation for future clinical trials.

3:45pm | A BAC transgenic mouse model for DM2

Presented by Laura Ranum, PhD – University of Florida

Myotonic dystrophy type 1 (DM1) and type 2 (DM2) are multisystemic diseases caused by CTG or CCTG repeat expansions located in the DMPK or CNBP genes, respectively. RNA gain of function effects, bidirectional transcription and repeat associated non-ATG (RAN) translation are found in both DM1 and DM2. RAN translation of sense (CCUG) and antisense (CAGG) expansion transcripts produce (LPAC) and (QAGR) RAN proteins. LPAC and QAGR proteins are toxic to cells and found in brain regions with neurodegenerative changes and white matter loss. Understanding the role of RAN proteins in DM2 and developing therapeutic approaches requires animal models that mirror DM2 patient disease features. Using a bacterial artificial chromosome (BAC) approach we generated two separate lines of DM2 BAC transgenic mice with initial repeat lengths of ~750 CCTGs. Both DM2 mouse lines contain the entire human CNBP gene with substantial flanking sequence. Southern blot analyses suggest a single insertion site in each line. Substantial intergenerational repeat instability and selective breeding have led to mice with expanded repeats ranging in size from ~450 to 1950 CCTGs. Similar to human DM2 patients, these mice have somatic instability, with differing patterns of expansion and contraction between tissues. CCUG RNA foci are detected in skeletal muscle and brain. Immunohistochemistry studies show sense LPAC and antisense QAGR proteins accumulate in various brain regions. DigiGait abnormalities have been found in the 75 line with ongoing testing on the 236 line. In summary, we have generated a novel DM2 BAC transgenic mouse model that shows substantial repeat instability, RNA foci and RAN protein aggregates. We are continuing to characterize these mice and hope that this model will provide a useful tool to better understand the molecular mechanisms of DM2 and to facilitate therapeutic strategies.

4:15pm | The promise of gene therapy for myotonic dystrophy: can it float above a sea of challenges?

Presented by Eric Wang, PhD – University of Florida

Gene therapies are rapidly advancing for numerous genetic diseases, including several neuromuscular and neurological indications. Recent successes in the clinic have created excitement about the potential for safe and effective one-and-done treatments. However, the drug development path has not been without setbacks, particularly for X-linked myotubular myopathy and Duchenne muscular dystrophy. I will present a frank discussion of obstacles that must be surmounted for gene therapy to become a reality for DM, along with an overview of therapeutic approaches suited for viral-based delivery and recent advances in the gene therapy field.

Saturday, September 10th

9:00am | Groups of Signs and Symptoms in adult-onset myotonic dystrophy type 1

Presented by Suzanne McDermott, PhD – City University of New York

Background: Myotonic dystrophy Type 1 (DM1) is the most common form of muscular dystrophy, and it is a chronic progressive condition. The signs and symptoms (S&S) of DM1 change over the clinical course, and a surveillance system that captures people with DM1 at all stages of their life course can identify the groups of S&Ss that typically present in the same individual over time. Objective: To group the S&S of DM1 that typically present in the same person during the course of their clinical care using surveillance from a six-site e cohort in the United States. Methodology: Clinical records of 228 individuals with DM1 from the Muscular Dystrophy Surveillance, Tracking, and Research Network (MD STARnet) were abstracted. Twenty-two S&S (mean: 7.4 per person) were grouped using exploratory and confirmatory factor analysis. Results: Three groups of S&S were identified. Group 1, corresponding to ‘Facial Weakness/Myotonia’ includes the two most frequently presented S&Ss. About 79% patients reported facial weakness and 64% reported myotonia. Group 2: Skeletal Muscle Weakness includes eight muscular S&S. Group 2 is more frequently reported by males and patients with an older age at onset. Group 3: Gastrointestinal distress/ Sleepiness includes four non-muscular related S&S and hand stiffness. Conclusions: This study identified three clinically meaningful groups of S&S recorded in medical records. The overlap of the groups of S&S highlights the multidimensional nature of DM1, and recognizing the constellation of S&S within each group can result in earlier suspicion of DM1.

9:20am | The Myotonic Dystrophy Clinical Research Network (DMCRN): observational studies as the foundation for clinical trials

Presented by Nicholas Johnson, MD – Virginia Commonwealth University & Jeffrey Statland, MD – University of Kansas Medical Center

Objective/Purpose of the presentation: To describe the myotonic dystrophy research network and key observational studies supporting clinical trial planning. Relevance to DM field: Observational studies form the foundation for clinical trial planning and help better define our clinical understanding of myotonic dystrophy to help improve care. Methods/Procedure used in the research of your presentation: Overview of the structure of the DMCRN and study design, outcomes, and results for key observational studies. Results or Major Findings: The DMCRN is made up of over 20 international academic myotonic dystrophy specialty centers with common evaluator and coordinator training.  Our original 6 center DMCRN study showed the ability to have consistent training of evaluators for measures of strength and function, and revealed the ability to detect small but significant changes in muscle strength and motor performance over 1 year.  Tibialis anterior muscle biopsies helped refine an index of splicing changes in muscle which can be used for early stage disease targeted clinical trials. An ongoing large 700 person observational study will validate findings of our first study, show the ability to collaborate internationally, and help identify and understand genetic modifiers influencing disease progression.  Additional network studies have performed parallel studies in congenital myotonic dystrophy. Conclusions/Future Work: Studies are ongoing on the DMCRN which is working hand in hand with all stakeholders to prepare the field for planned and ongoing clinical trials.

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