Genetic Muscle Disorders Research

Clinical Research:

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.

A Phase 2 Randomized, Double-Blind, Placebo-Controlled, Multiple Ascending Dose Study to Evaluate the Safety, Efficacy, Pharmacokinetics and Pharmacodynamics of PF-06252616 in Ambulatory Boys with Duchenne Muscular Dystrophy (DMD)

Johns Hopkins IRB Protocol Number: IRB00049415
Principal Investigator: Kathryn Wagner, M.D., Ph.D.
Status: Active, recruiting

We have started enrolling in this multicenter, Phase 2 randomized, two-period, double-blind, placebo-controlled, multiple ascending dose study sponsored by Pfizer, Inc. The study is designed to evaluate the safety, efficacy, drug levels, and drug activity of a new study drug, PF-06252616. The study drug is a myostatin inhibitor, and myostatin is one of the main factors that prevents muscle growth. The goal of the study is to demonstrate a functional improvement in timed motor testing in boys with DMD who are given IV doses of PF-06252616 as compared to placebo, following 49 weeks of treatment.

Eligible participants are randomly assigned to one of three groups. Three dose levels (5, 20, 40 mg/kg) will be administered via an IV infusion every 4 weeks for approximately 96 weeks.

Males who are able to walk, between the ages of 6 years to less than 10 years old, with confirmed DMD mutations are eligible. Participation in the research study requires out-patient visits. Travel funds are available. View the research study flyer.

Related Link: - NCT02310763

An Open-Label Extension Study to Evaluate the Long-Term Safety, Tolerability and Efficacy of Drisapersen in US and Canadian Subjects with Duchenne Muscular Dystrophy (DMD115501)

Johns Hopkins IRB Protocol Number: IRB00046817
Principal Investigator: Kathryn Wagner, M.D., Ph.D.
Status: Active, recruiting

This phase III, multicenter, open-label, uncontrolled extension study, sponsored by Prosensa Therapeutics, is open to male subjects with DMD open to eligible US or Canadian subjects who previously participated in the following studies of drisapersen: DMD114876, DMD114044, and DMD114349. Study participants will receive drisapersen 6 mg/kg as subcutaneous (SC) injection(s) once a week. For subjects who have previously experienced significant safety or tolerability issues in one of the eligible studies, or who experience these during this study, there is the potential of an alternate intermittent dosing arm. This study does not have a minimum duration of participation. Participants will be allowed to continue in this study until they withdraw based on protocol defined criteria or when Prosensa (the sponsor) stops the study. The study is expected to end if the study drug, drisapersen, receives FDA approval.

Related Link: - NCT01803412

An Open-Label, Multi-Center, 48-Week Study with Concurrent Untreated Control Arm to Evaluate the Efficacy and Safety of Eteplirsen in Duchenne Muscular Dystrophy

Johns Hopkins IRB Protocol Number: IRB00040305
Principal Investigator: Kathryn Wagner, MD, PhD
Status: Active, recruiting

This open-label, Phase 3, multi-center, 48-week study, sponsored by Sarepta Therapeutics, evaluates the efficacy and safety of a new study drug, eteplirsen, in patients with Duchenne muscular dystrophy (DMD) with genetic deletions amenable to correction by exon 51 skipping (treated group). Eteplirsen is designed to “skip” a part of the gene that makes dystrophin called exon 51. For people who have changes, called deletions, in certain parts of the dystrophin gene, skipping exon 51 might potentially allow the body to produce a shortened, but still working, form of the dystrophin protein. The research study will test whether eteplirsen works to improve muscle function in people with DMD who have deletions that may be corrected by skipping exon 51. Eteplirsen, 30mg/kg, will be given via intravenous infusion once a week for 48 weeks. The study will also have an untreated control group which will include DMD patients with genetic deletions not amenable to exon 51 skipping. Male participants with confirmed DMD mutation must be between 7 to 16 years of age and able to walk. Participation in the research study requires out-patient visits. View the research study flyer.

Related Link: - NCT02255552

An Open-Label Extension Study to Evaluate the Safety, Tolerability and Efficacy of Eteplirsen in Patients with Advanced Stage Duchenne Muscular Dystrophy ((Protocol Number 4658-204)

Johns Hopkins IRB Protocol Number: IRB0005643
Principal Investigator: Kathryn Wagner, M.D., Ph.D.
Status: Active, not recruiting

This is an open-label, Phase 2, multi-center study sponsored by Sarepta Therapeutics designed to explore the safety and tolerability of eteplirsen injection in patients with advanced stage DMD with confirmed genetic mutations amenable to treatment by exon 51 skipping. This research study will test whether eteplirsen works to improve muscle function and to find out if eteplirsen is safe to take without causing too many side effects. Eligible patients will receive once weekly intravenous (IV) infusions of 30 mg/kg eteplirsen for up to 96 weeks. Participation in the research study requires out-patient visits. An extension to the dosing period may be considered prior to the end of the 96-week planned dosing period. Safety will be regularly assessed throughout the study via the collection of adverse events, laboratory tests, electrocardiograms (ECGs), echocardiograms (ECHOs), vital signs, and physical examinations. Exploratory efficacy assessments, including pulmonary function testing (PFTs), upper extremity testing, and other measurements of functional status, will occur at functional assessment visits every 12 weeks over the first year of treatment and approximately every 24 weeks over the second year of treatment.

Related Link: – NCT02286947

Bone Health in Facioscapulohumeral Muscular Dystrophy (FSHD): A Cross-Sectional Study

Johns Hopkins IRB Protocol Number: IRB00031738
Principal Investigator:
 Kathryn Wagner, MD, PhD
Status:  Active, Recruiting

FSHD individuals have reduced muscle mass and strength and concomitantly may affects bone mineral density. There are no medical guidelines for bone health screening and treatment in FSHD patients. This study aims to address this need in the FSHD community by performing a cross-sectional study of bone health in adults with FSHD. This is a single visit study involving routine neurological evaluation of muscle strength testing, timed function tests in ambulatory participants, whole body DEXA scan for bone mineral density and lean body mass, and serum biomarkers of bone health. The procedures will be paid through a grant from FSHD Global Research Foundation. View Research Study Flyer

Related Link: - NCT02413190

Collection of Data from Muscle Strength Testing

Johns Hopkins IRB Protocol Number: NA_00082223
Principal Investigator:
 Kathryn Wagner, MD, PhD
Status:  Active, Recruiting

This observational, cross-sectional study aims to collect data on muscle strength and function for informed clinical trial designs. The data will be collected from patients with  muscular dystrophy during their visits at the Kennedy Krieger Institute Out-patient Center. We will request participants to share the results of their clinical muscle strength testing to be entered in a research database. The muscle strength testing is routinely performed during a neurological evaluation and is a standard of care procedure. 

Genetic Modifiers of Conduction Disease Risk in Myotonic Dystrophy

Johns Hopkins IRB Protocol Number: NA_00048833
Principal Investigator:
Saman Nazarian, MD
Co-Principal Investigator: Kathryn Wagner: MD, PhD
Status: Active, Recruiting

This multi-center case controlled observational study is established to determine if genetic variants that are known to modulate cardiac conduction and arrhythmia risk in the general population are associated with risk of ECG abnormalities in myotonic dystrophy. Patients with type I myotonic dystrophy with or without electrocardiographic abnormalities will be recruited. Blood samples will be collected for focused genetic analysis.

Biomarkers of Facioscapulohumeral Muscular Dystrophy (FSHD)

Johns Hopkins IRB Protocol Number: NA_00019985
Principal Investigator: Kathryn Wagner MD, PhD
Status: Active, Recruiting

This NIH-funded study is established to identify biomarkers for facioscapulohumeral muscular dystrophy (FSHD). FSHD patients and their unaffected first degree relative will undergo open muscle biopsy performed at the Johns Hopkins Outpatient Surgery Center under local anesthesia. Blood samples will be drawn from each subject to establish DNA and lymphhocyte repositories, as well as for FSHD A/B allele genotyping. A new focus on FSHD families with nonmanifesting carriers of the genetic signature will expand on the usefulness of our repository by providing DNA from blood, muscle biopsy tissue and cells derived from biopsies for investigating modifiers of FSHD pathology. De-identified muscle and blood samples will be sent to the Senator Paul D. Wellstone FSHD Muscular Dystrophy Cooperative Research Center for storage, processing and distribution to multiple institutions involved in FSHD research. The biomaterials obtained at Kennedy Krieger are studied in multiple labs and are anticipated to significantly improve the molecular understanding of this enigmatic disease. Travel funds are available. View Research Study Flyer.

Magnetic Resonance Imaging and Spectroscopy Biomarkers for Facioscapulohumeral Muscular Dystrophy

Johns Hopkins IRB Protocol Number: NA_00065256
Principal Investigator: Kathryn Wagner, MD, PhD
Status: Recruiting

This study, supported by the FSH Society, will utilize magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) to develop non-invasive, quantitative imaging biomarkers for facioscapulohumeral muscular dystrophy (FSHD), a genetic disorder that causes progressive skeletal muscle atrophy. The primary objective of this protocol will be to perform muscle MRI and MRS on groups of subjects with FSHD and control subjects. The imaging protocols employed in this study will be developed in a collaborative effort between resarchers at the Center for Genetic Muscle Disorders at the Kennedy Krieger Institute and Department of Radiology and Radiological Sciences at Johns Hopkins Hospital. Imaging and spectroscopic measurements will be correlated with muscle strength testing measurements to identify biomarkers that accurately reflect disease severity. In order to confirm that these biomarkers are specific for FSHD, both healthy and diseased controls will be enrolled. The successful characterization of imaging and spectroscopy biomarkers in FSHD will provide a powerful, non-invasive tool for future therapeutic trials in FSHD. Travel funds are available. View Research Study Flyer.

Related Link: – NCT01671865

HALO-DMD-01:  A Phase 1b Open Label, Single and Multiple Ascending Dose Study to Evaluate the Safety, Tolerability, and Pharmacokinetics (PK) of HT-100 in Patients with Duchenne Muscular Dystrophy

Johns Hopkins IRB Protocol Number:  NA__00082081
Principal Investigator: Kathryn Wagner, MD, PhD
Status:  Active, not recruiting

The study, sponsored by HALO Therapeutics, is designed to provide initial safety, tolerability, and PK data of halofuginone hydrobromide, HT-100, in young boys ages 6-20 years with DMD.  HT-100 is a delayed released, orally-delivered anti-fibrotic and anti-inflammatory agent.  Specifically, the current trial is designed to provide a complete PK plasma profile following administration of single and multiple doses of HT-100 in study participants assigned in 1 of 5 cohorts and administered in dose-escalating fashion. The multiple ascending dose phase of the study (1 week dosing followed by a minimum 1 week wash out) will continue with 4 weeks of open-label dosing to evaluate safety and early pharmacodynamics signals in this broad DMD population. After completion of the MAD phase of this study, participants will be eligible to enroll in a 6-month open label extension study. Travel assistance is available. View Research Study Flyer.

Related Links: - NCT01847573

HALO-DMD-02:  An Open Label Extension Study of HT-100 in Patients with Duchenne Muscular Dystrophy who have Completed Protocol HALO-DMD-01

Johns Hopkins IRB Protocol Number: NA__00086591
Principal Investigator: Kathryn Wagner, MD, PhD
Status:  Active, not recruiting 

This open-label, multiple dose extension study is designed to evaluate the safety, tolerability, pharmacodynamic signals, and population PK of HT-100, a delayed-release, orally-delivered agent in participants with DMD. Study subjects will have completed Protocol HALO-DMD-01. To avoid an interruption in dosing, each consented participant will undergo the screening assessments at the time of the Month 1 Follow-up/Exit Visit of the predecessor trial, HALO-DMD-01. Participants who fulfill all eligibility criteria will be entered into the extension protocol that same day and will resume dosing with HT-100 at the same dose level as previously assigned in HALO-DMD-01. This extension study is designed to provide data on continuous, chronic (6 months) dosing. Data from this study will be subsequently used to inform the safety, tolerability, and dose selection for a future trial of HT-100 in boys with DMD.  Travel assistance is available.

Related Links: - NCT01978366

HALO-DMD-03: HT-100 Long-Term Safety And Pharmacodynamics In Patients With DMD Who Have Completed Protocols HALO-DMD-01 and HALO-DMD-02 (HALO-DMD-03)

Johns Hopkins IRB Protocol Number: IRB00068303
Principal Investigator: Kathryn Wagner, M.D., Ph.D.
Status: Active, not recruiting

HALO-DMD-03 is a follow-on study to two IRB approved studies HALO-DMD-01 (NA_00082081) and HALO-DMD-02 (NA_00086591), and allows continued open-label access to HT-100 for subjects who have completed these studies. HALO–DMD-03 will provide safety and PD data on continuous long-term dosing. Data from this study will subsequently be used to inform the safety, tolerability, and dose selection for a future trial of HT-100 in boys with DMD. This continuation study is sponsored by Akashi Therapeutics, LLC (formerly HALO Therapeutics, LLC).

A Phase 1/2a Blinded, Placebo-Controlled Study to Assess the Safety, Tolerability, and Dose-range Finding of Multiple Ascending Doses of ISIS 598769 Administered Subcutaneously to Adult Patients with Myotonic Dystrophy Type 1(DM1)

Johns Hopkins IRB Protocol Number: IRB00052515
Principal Investigator: Doris Leung, M.D.
Status: Active, recruiting

This is a phase 1/2a multi-center, blinded, placebo-controlled, randomized, multiple ascending dose study to examine the safety and tolerability of multiple doses of ISIS 598769 administered subcutaneously to adult patients ages 20-55 years of age with genetic confirmation of DM1. Approximately 36 subjects (4 dose cohorts; 8 subjects per cohort in first 3 cohorts, 12 subjects in the highest dose cohort) are planned to be enrolled into this multiple-dose study of ISIS 598769. The number of subjects may be higher if subjects must be replaced and/or if the size or number of the cohorts is expanded in order to obtain further experience with some dose levels. The maximum number of enrolled subjects could range between 36 and 48 subjects. The length of each subject’s participation in this study is approximately 24 weeks (~ 6 months) which includes a 4-week screening period, a 6-week treatment period, and a 14-week post-treatment evaluation period. Subjects will receive a total of 8 SC doses of Study Drug.

Related link: - NCT02312011

For More Information

If you are interested and would like more information about the clinical research studies, contact Genila Bibat, MD, at or call (443) 923-2697.

Laboratory Research:

Lab Mice

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.

Myostatin Regulates Fate of Satellite Cells in Dystrophic Muscle (Muscular Dystrophy Association)

Principal Investigator: Kathryn Wagner, MD, PhD

The goal of this proposal is to determine whether myostatin, expressed in both skeletal muscle and fibroblasts, regulates the conversion of satellite cells to fibroblasts and whether this conversion contributes to fibrosis prominent in dystrophic muscle. First, we will determine the ability of myostatin to induce the conversion of satellite cells to fibroblasts in an animal model of dystrophic muscle. Second, we will investigate the ability of myostatin to induce fibrogenic converfsion of human satellite cells isolated from both normal and muscular dystrophy subjects. Third, we will investigate whether cross-talk between myostatin signaling and wnt signaling, which stimulates stem cell differentiation into myogenic lineage is involved int eh conversion of muscle satellite cells from a myogenic to fibrogenic lineage. The knowledge obtained by this study will be important in the application of new myostatin inhibitors currently in trials for muscular dystrophy.

Partnering to Treat an Orphan Disease Duchenne Muscular Dystrophy (NIH/NCATS)

Principal Investigator: Kathryn Wagner, MD, PhD

The goal of this program is to develop an investigational drug by Sanofi for a new indication, Duchenne Muscular Dystrophy.  The program includes preclinical toxicology and efficacy studies as well as Phase 1 and Phase 2a studies in DMD. We propose to repurpose a Sanofi drug which is an oral, soluble guanylate cyclase (sGC) activator with an excellent safety and tolerability profile. It has been shown that modulation of the NO-cGMP pathway improves cardiac and skeletal muscle function in the mdx mouse model of DMD. The study now propose to determine if this Sanofi drug, which acts downstream of PDE inhibitors, provides benefit to DMD. The pre-clinical study will test efficacy of the drug in the mdx/utr mouse model of DMD and juvenile toxicology studies will be performed. Following IND filing with the FDA, a Phase Ib SAD/ MAD/extension study will be performed in 3 sites for safety and dose finding in a limited number of DMD subjects. Following this, a Phase IIb study in 5 clinical sites will determine if the drug will result in functional improvement in DMD as well as whether its sustained administration is safe and well tolerated in DMD. Given the life-threatening and disabling nature of DMD the Phase IIb is anticipated to be the pivotal clinical trial for seeking provisional FDA approval.

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.