The Center for Genetic Muscle Disorders conducts innovative research in neuromuscular disorders affecting children and adults. We interact closely with other clinical researchers and basic scientists to understand disease mechanisms so as to ultimately provide novel treatments. While the genetic basis is known for most genetic muscle disorders, there are no cures and patients have few treatment options. Active participation in research programs allows the Center to better serve patients by providing direct access to potential trials for which they may be eligible.

Magnetic Resonance Imaging and Spectroscopy Biomarkers for Facioscapulohumeral Muscular Dystrophy

Johns Hopkins IRB Protocol Number:  NA_00065256
Principal Investigator:  Doris Leung, M.D., Ph.D.
Status:  Active, recruiting

This is clinical research study that will utilize magnetic resonance imaging and spectroscopy to identify unique musculoskeletal imaging profiles in the subjects with facioscapulohumeral muscular dystrophy (FHSD) compared to healthy volunteers and individuals with other forms  of skeletal muscle disease. A subset of individuals with FSHD will be enrolled in a longitudinal cohort study to track changes in imaging and spectroscopy over time.


A Phase 2, Randomized, Double-Blind, Placebo-Controlled, 48-Week, Parallel-Group Study of the Efficacy and Safety of Losmapimod in Treating Subjects with Facioscapulohumeral Muscular Dystrophy (FSHD) with Open-Label Extension (OLE)

Johns Hopkins IRB Protocol Number: IRB00212675
Principal Investigator: Doris Leung, M.D., Ph.D.
Status: Active, not recruiting

This is a multi-site, randomized, double-blind, placebo-controlled study to determine whether an investigational study drug called losmapimod may slow down or stop the progression of the disease in individuals with facioscapulohumeral muscular dystrophy (FSHD). The study, sponsored by Fulcrum Therapeutics, enrolled ambulatory adults with FSHD. The initial 48-week double-blind phase was followed by an open-label extension period where all participant are receiving losmapimod.

Related Link:  ClinicalTrials.gov - NCT 04264442


A Randomized, Double Blind, Placebo-Controlled Phase 1b Study With Open-Label Extension to Assess the Safety, Tolerability and Preliminary Efficacy of ASP0367 (MA-0211) in Pediatric Male Patients with Duchenne Muscular Dystrophy (DMD)

Johns Hopkins IRB Protocol Number: IRB00234958
Principal Investigator: Doris Leung, M.D., Ph.D.
Status: Active, recruiting

This randomized, double-blind, placebo-controlled phase 1b study with open-label extension (OLE) will focus on assessing safety, tolerability and preliminary efficacy of the study drug ASP0367 (also called as MA-0211). The participants in this study will be late ambulatory and early non-ambulant patients with DMD ages 8-16 years. DMD boys have dysfunctional mitochondria which in turn inhibits muscle repair. By increasing or enhancing mitochondria in muscle cells, muscle repair could be improved.

Preliminary efficacy will be assessed utilizing the assisted 6-minute cycling test (a6MCT), a motor assisted cycling test for arms that can be used for DMD subjects who have recently become wheelchair dependent. This study is comprised of a 4-week Pretreatment Screening Period, 24-week Treatment Period, and 4-week Post-treatment Follow-up Period. The 24-week Treatment Period consists of a 12-week double-blind (DB) part and 12-week OLE part and each part includes a 2-week Low-dose Period and a 10-week High-dose Period. Approximately 18 subjects will be enrolled in the study sponsored by Astellas Pharma, Inc.

Related Link:   ClinicalTrials.gov - NCT04184882


A Randomized, Double-Blind, Placebo-Controlled, Multiple Dose Study with an Open-Label Extension to Determine the Safety, Pharmacokinetics and Efficacy of Oral Ifetroban in Subjects with Duchenne Muscular Dystrophy

Johns Hopkins IRB Protocol Number: IRB00257427
Principal Investigator: Doris Leung, M.D., Ph.D.
Status: Active, recruiting

This is a phase 2 study for males with Duchenne Muscular Dystrophy (DMD) ages 7 years and above which aims to determine the safety and efficacy of an investigational drug, ifetroban, in the heart of patients with DMD. Participants will have an equal chance of being assigned to any of the three groups (low dose ifetroban, high dose ifetroban, or placebo). Ifetroban targets cardiac muscle by cardiomyocyte protection and improving heart function.

Participants will be in this study for about 12 months where they will be asked to come to our Site four times. There is an optional 12-month extension in which all participants will receive ifetroban. The study drug will be in capsule form. Approximately 48 subjects will be enrolled in the study sponsored by Cumberland Pharmaceuticals, Inc.

Related Link:  ClinicalTrials.gov - NCT03340675


A Phase 3, Randomized, Double-Blind, Trial of Pamrevlumab (FG-3019) or Placebo in Combination with Systemic Corticosteroids in Subjects with Non-ambulatory Duchenne Muscular Dystrophy (DMD) (PROTOCOL NO.:FGCL-3019-093) – LELANTOS ONE

Johns Hopkins IRB Protocol Number: IRB00259168
Principal Investigator: Doris Leung, M.D., Ph.D.
Status: Active, recruiting

This is a global, randomized, double-blind trial of pamrevlumab or placebo in combination with systemic corticosteroids in non-ambulatory males Duchenne muscular dystrophy, aged 12 years and older. Pamrevlumab is a type of protein drug called a human monoclonal antibody. It may help reduce fibrosis and thereby decreasing the breakdown of mature muscle cells and increase muscle strength.

Approximately 90 subjects will be randomized at a 1:1 ratio to Arm A (pamrevlumab + systemic corticosteroid) or Arm B (placebo + systemic corticosteroid), respectively. During the treatment period, each subject will receive pamrevlumab or placebo at 35 mg/kg every 2 weeks for up to 52 weeks. Subjects who complete the 52-week study (either arm) may be eligible for rollover into an open-label extension treatment (OLE) with pamrevlumab + systemic corticosteroids. This clinical trial is sponsored by FibroGen, Inc.

Related Link: ClinicalTrials.gov - NCT04371666


A Phase 3, Randomized, Double-Blind, Trial of Pamrevlumab (FG-3019) or Placebo in Combination with Systemic Corticosteroids in ambulatory subjects with Duchenne Muscular Dystrophy (DMD): Protocol FGCL-3019-094 --  LELANTOS TWO

Johns Hopkins IRB Protocol Number: IRB00276612
Principal Investigator: Doris Leung, M.D., Ph.D.
Status: Active, recruiting

The purpose of this study is to determine the safety and efficacy of an investigational study drug, pamrevlumab, with systemic corticosteroids in ambulatory individuals with Duchenne Muscular Dystrophy (DMD). Pamrevlumab is a type of protein drug called a human monoclonal antibody. It may help reduce fibrosis and thereby decreasing the breakdown of mature muscle cells and increase muscle strength.

About 70 participants are expected to enroll in the study which will last for approximately 64 weeks. Participants will be assigned to 1 of 2 treatment arms: Group A: pamrevlumab+ corticosteroid or Group B: placebo (an inactive material that does not contain any active study drug) + corticosteroid. There is an open label extension period where all participants will receive pamrevlumab. This clinical trial is sponsored by FibroGen, Inc.

Related Link: ClinicalTrials.gov - NCT04632940


A Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Safety  and Efficacy of Pitolisant on Excessive Daytime Sleepiness and Non-Muscular Symptoms in Patients with Myotonic Dystrophy Type 1, Followed by an Open- Label Extension (Protocol Number: HBS-101-CL-005)

Johns Hopkins IRB Protocol Number: IRB00284821
Principal Investigator: Doris Leung, M.D., Ph.D.
Status: Active, recruiting

The purpose of this research study is to learn about the safety and effectiveness of a study drug called pitolisant when compared with placebo in treating some of the symptoms of myotonic dystrophy type 1 (DM1), such as excessive daytime sleepiness. Patients with DM1, ages 18-65 years, who are able to walk independently with or without an assistive device can participate.

This study consists of a double-blind period in which participants may receive pitolisant or placebo, and an open-label period in which all participants will receive pitolisant. The double-blind period will last for up to about 21 weeks and the open-label extension period is expected to last multiple years. Participants will stay the night at the clinic twice during the study before a test done in the sleep lab that starts early the next morning. The clinical trial is sponsored by Harmony Biosciences, LLC.

Related Link: ClinicalTrials.gov - NCT04886518


Motor Outcomes to Validate Evaluations in FSHD (MOVE FSHD)

Johns Hopkins IRB Protocol Number: IRB00275226
Principal Investigator: Doris Leung, M.D., Ph.D.
Status: Active, recruiting

The primary goal of this study is to collect motor and functional outcomes specific to facioscapulohumeral muscular dystrophy (FSHD) over time. This will help ensure that the best level of clinical care is provided. Another hope is to speed up drug development by gaining a better understanding of how having FSHD impacts your motor function and other health outcomes (i.e. your breathing) and how big a change in motor function would be clinically meaningful. A total of 250 patients, genetically confirmed FSHD (types 1 or 2) or clinical diagnosis of FSHD with characteristic findings on exam and an affected parent or offspring, from different participating sites will be followed for 3 years. This is a reliance study with University of Kansas Medical Center (KUMC).

Related Link: ClinicalTrials.gov - NCT04635891


A Long-term Observational Study Evaluating Sarepta Therapeutics, Inc.’s Exon-Skipping Therapies in Patients with Duchenne Muscular Dystrophy under Conditions of Routine Clinical Practice (Protocol 4658-403)

Johns Hopkins IRB Protocol Number: IRB00195928
Principal Investigator: Doris Leung, M.D., Ph.D.
Status: Active, recruiting

Duchenne muscular dystrophy (DMD) patients being treated by their clinic doctor with Sarepta’s exon skipping therapies may participate. This observational study aims to collect long-term medical information from DMD patients receiving eteplirsen or, golodirsen, or casimersen. Medical information from routine clinical care will be obtained for a minimum of 5 years. There will be no additional medical procedures. There is no direct benefit to participants from being in this study. but the study hopes to learn more about patients being treated with these exon skipping therapies. This study is sponsored by Sarepta Therapeutics, Inc.


Biomarker Development in LGMD 2i

Johns Hopkins IRB Protocol Number: IRB00235297
Principal Investigator: Doris Leung, M.D., Ph.D.
Status:  Active, not recruiting

The purpose of this natural history study is to learn more about limb girdle muscular dystrophy (LGMD) 2I and what effects it has on patients during disease progression. The study aims to know which clinical outcome assessments will best assess the functional capabilities of patients with LGMD2I. Participants will be asked to come to our site 5 times over approximately 12 months. There are some risks to the procedures including a needle muscle biopsy. ML Bio Solutions is sponsoring this research study.

Related Link: ClinicalTrials.gov - NCT04202627


Clinical Trial Readiness to Solve Barriers to Drug Development in FSHD (RESOLVE)

Johns Hopkins IRB Protocol Number: IRB00158125
Principal Investigator: Doris Leung, M.D., Ph.D.
Status: Active, not recruiting

This 24-month longitudinal multi-site FSHD study aims to hasten drug development by validating clinical outcome assessments: 1) an evaluator-administered functional composite (FSHD-COM) composed of disease-relevant standard functional tasks, and 2) electrical impedance myography (EIM), a non-invasive physiological biomarker for measuring changes in muscle composition. There will be 150 participants, genetically confirmed FSHD1 or clinical diagnosis of FSHD with characteristic findings on exam and an affected parent or offspring ages 18-75 years. This large prospective study will simultaneously allow us to re-assess the rate of disease progression of FSHD in light of specific demographic and genetic factors that may influence how to define criteria for trial eligibility. This is a reliance study with University of Kansas Medical Center (KUMC).

Related Link: ClinicalTrials.gov - NCT03458832


Defining Clinical Endpoints in LGMD

Johns Hopkins IRB Protocol Number: IRB003981289
Principal Investigator: Doris Leung, M.D., Ph.D.
Status: Active, recruiting

The purpose of this multi-site natural history study is to learn more about Limb Girdle Muscular Dystrophy (LGMD). The study aims to define clinical outcome assessments (COAs) where LGMDs converge and diverge in performance. This will help hasten therapeutic development and ensure properly powered clinical trials. Participation in this study will last anywhere from 1 day to 12 months. There will be about 184 participants ages 4-65 years. The following are sponsoring this study: Coalition to Cure Calpain, Sarepta Therapeutics, Muscular Dystrophy Association.

Related Link:  ClinicalTrials.gov - NCT03981289


Assessing Arrhythmic Risk in Patients with Duchenne Muscular Dystrophy.

Johns Hopkins IRB Protocol Number: IRB00214313
Principal Investigator: Andreas Barth, M.D., Ph.D.
Status: Active, recruiting

This multi-site observational cohort study aims to collect data related to arrhythmias of patients 10 years of age or older with Duchenne muscular dystrophy (DMD). This study will include DMD males, 10 years and older, who have undergone prolonged ambulatory EKG monitoring (Ziopatch and event monitors or prior implantation of a loop recorder [ILR]). Retrospective medical record review and prospective collection of clinical data will be conducted. In addition, to learn about the relationship between ventricular and atrial arrhythmias with myocardial fibrosis, computer simulations with personalized 3D heart models generated from cardiac MRI images (obtained as part of clinical standard of care) will examine whether scar tissue found in DMD hearts will allow for a better identification of patients at highest risk for ventricular tachyarrhythmias. About 75 DMD patients will participate in this study sponsored by the Department of Defense.


Laboratory Research

Histochemical and morphometric analysis of FSHD biceps

Principal Investigator:  Kathryn Wagner, M.D., Ph.D.

This grant is to study the histopathological features of muscle in the largest biobank to date from FSHD patients and their first degree family members.  By establishing a detailed morphometric signature of FSHD, we will be able to develop muscle pathology as an outcome measure in future clinical trials.  Further, by correlating specific features such as degeneration and inflammation with DUX4 expression, we will be able to determine whether DUX4 has a primary or secondary effect on muscle pathology.


Development of new potent AAV vectors for gene transfer to human muscle (SOLID GT)

Principal Investigator:  Kathryn Wagner, M.D., Ph.D.

We have developed a library of chimeric AAV capsids generated by DNA shuffling of 11 AAV capsid genes, and in vivo screening in wild-type mice has yielded new capsids with enhanced muscle tropism. The new AAV-B1 capsid appears to be at least 10-fold more efficient than AAV9 for muscle gene transfer in wild type mice (Fig. 1). We have also tested the AAV-B1 capsid in a unique model of in vivo human skeletal muscle. Human muscle xenografts are vascularized and innervated in immunodeficient mice and can be transduced with systemic administration of AAV (Fig. 2). . The novel AAV capsid library has been infused systemically into mice humanized with skeletal muscle to screen for high efficiency capsids for gene transfer to human skeletal muscle. We have amplified numerous chimeric capsid genes from the human muscle xenografts. The new capsids are highly homologous to AAV-B1 but nonetheless carry several differences throughout VP1, VP2 and VP3 regions of the CAP gene. We don’t believe this is due to a bias in the library as capsids amplified from mouse liver are quite different from AAV-B1 and each other at high doses.

Our goal is to characterize the tropism of the new AAV capsids identified from human muscle and compare their efficiency against AAV capsids currently being developed for muscle gene therapy.


A Novel Xenograft Mouse Model of Facioscapulohumeral Muscular Dystrophy  (NIH/NINDS)

Principal Investigator : Kathryn Wagner, MD, PhD

The goal of this study is to construct and validate an animal model of FSHD derived from human muscle. Despite being one of the most prevalent neuromuscular disorders worldwide, there have been very few clinical trials in Facioscapulohumeral muscular dystrophy (FSHD). Currently there are no clinical trials and no good therapeutic options for this progressively disabling disease. One of the main impediments to the development of novel drugs for FSHD is the lack of an accepted animal model stemming from an incomplete understanding of the pathogenesis of the disease. The study proposes to develop a novel animal model of FSHD which is independent of any hypothesis of pathogenesis. In this model, muscle tissue from subjects with FSHD are transplanted into the hindlimbs of immunodeficient, NOD- Rag1null IL2rγnull  mice. Preliminary data indicate that these xenografts are vascularized and innervated by the mouse host. Human myoblasts fully regenerate the tissue with new myofibers which survive in vivo through 20 weeks post transplantation. Feasibility has been established with dozens of recent and prospective human donors and the ability to generate approximately 20 xenografts from a single open muscle biopsy. The first aim of this proposal is to optimize the xenograft by determining the maximal size of human graft which is viable in this model and the minimum amount of time from transplantation until full regeneration of the human graft in the mouse host. Use of nerve translocation as well as myostatin inhibition to optimize the graft will be critically assessed. The second aim of the proposal is to validate the xenograft as a model of FSHD and to fully characterize it for future use in preclinical studies. In this aim, grafts will be evaluated for their histopathological, physiologic and molecular (gene expression) characteristics. FSHD Xenografts will be compared to the biopsy specimen from which they originated and to xenografts of normal muscle from biologically related donors. The product of this work will be a fully characterized xenograft model of FSHD as well as standard operating procedures for evaluating this model in preclinical drug studies. Such studies are expected to facilitate entry of novel therapeutics into clinical trials for FSHD which is currently an underserved disease population.


A Three Dimensional Environment for Skeletal Muscle Stem Cell Transplantation (Maryland Technology Development Corporation)

Principal Investigator : Kathryn Wagner, MD, PhD 

The purpose of this collaborative project is to develop and test and injectable scaffold embedded with muscle stem cells and a Pfizer drug to facilitate muscle regeneration. Cell based therapies lag behind the development of other approaches to chronic muscle disease including gene therapy and pharmacological therapies. However, it is commonly believed that cell therapies will provide the eventual cures to chronic inherited and acquired muscle disease such as muscular dystrophy and sarcopenia. Skeletal muscle is composed of syncytial multinucleated myofibers in a fairly simple cellular organization suggesting that stem cell therapy should be quite feasible. Indeed, animal studies have shown engraftment of muscle stem cells and amelioration of disease phenotype. However, previous clinical trials in disease patients have been disappointing. Recognizing that the environment as well as the stem cells needs to be optimized, a collaborative team, composed of muscle biologist and neuromuscular clinician, bioengineer, and stem cell biologist, proposes to develop a three dimensional environment for muscle stem cell transplantation. The Specific Aims of the proposal are to 1) optimize an injectable, biosynthetic scaffold for skeletal muscle stem cell transplantation, 2) embed novel myostatin inhibitors obtained by a collaboration with Pfizer in the biosynthetic scaffold to stimulate muscle stem cells to proliferate and differentiate into myofibers and 3) isolate and derive various human muscle stem cells including satellite cells, pericytes and skeletal muscle cells derived from hiPSCs from human volunteers. The human muscle stem cells will then be seeded on optimized scaffold with embedded myostatin blocker and transplantation efficiency will be assessed in immunodeficient mice. These experiments will provide important knowledge on requirements of biosynthetic scaffolds, properties of various human muscle stem cells and the growth conditions needed to facilitate their transplantation and engraftment to achieve effective skeletal muscle regeneration.


Biomarkers for Therapy of FSHD (NIH/NICHD)

Principal Investigator : Kathryn Wagner, MD, PhD

The goal of this Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Center is to define modifying genes of FSHD and to determine, through novel animal models of FSHD, whether these are appropriate therapeutic targets. 1) Our current research will seek to identify genetic modifiers of Facioscapulohumeral muscular dystrophy by focusing on nonmanifesting earners of the 4qA allele. These individuals suggest that the current genetic signature of FSHD (D4Z4 contraction in the presence of the 4qA allele and a polyadenylation sequence in a distal pLAM sequence) is not an exclusive determinant of FSHD and that there is either a "second-hit" resulting in disease or a protective gene resulting in muscle health. 2) In the animal models of FSHD, our research aims to use xenografts of mouse and human muscle as well as a zebrafish model of DUX4 misexpression during development. The humanized mouse muscle either by direct engraftment of human skeletal muscle or with cell transplantation provides human muscle in a living organism on which to develop therapeutic approaches. The models should allow the search for modulators of DUX4-fl expression and any key developmental targets of DUX4-fl expression. In addition, the latter should result in an understanding of the generation of clinical symptoms outside skeletal muscle. Knock down of Dux4-fl through AAV as well as morpholino administration will be developed in the xenografts with the ultimate goal of using these approaches in clinical trials.