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 Multi-Site, Randomized, Placebo-Controlled, Double-Blind, Multiple Ascending Subcutaneous Dose Study to Evaluate the Safety, Tolerability and Pharmacokinetics of BMS-986089 in Ambulatory Boys with Duchenne Muscular Dystrophy

Johns Hopkins IRB Protocol Number:  IRB0007788
Principal Investigator:  Kathryn Wagner, M.D., Ph.D.
Status:  Active, not recruiting

This is a multi-site, randomized, placebo-controlled, double-blind, multiple ascending subcutaneous dose Phase 1b/2 study,  sponsored by  Bristol Myers Squibb. The study is being done to study the safety and tolerability of the investigational drug BMS-986089, a potent inhibitor of myostatin, in ambulatory boys with genetically confirmed Duchenne Muscular Dystrophy (DMD). Boys aged 5-10 years with DMD may join. The initial 24 week double blind phase will be followed by a 48 week open-label phase. During the open-label phase, all subjects will receive weekly subcutaneous doses of BMS-9860889 for 48 weeks at the active dose corresponding to the originally assigned panel.

Related Link: - NCT02515669


A Randomized, Double-Blind, Placebo-Controlled, Dose-Titration, Safety, Tolerability, and Pharmacokinetics Study Followed by an Open-Label Safety and Efficacy Evaluation of SRP-4045 in Advanced-Stage Patients with Duchenne Muscular Dystrophy Amenable to Exon 45 Skipping

Johns Hopkins IRB Protocol Number:  IRB00079233
Principal Investigator:  Kathryn Wagner, MD, PhD
Status:  Active, not recruiting

This multi-center, randomized, double-blind, placebo-controlled, dose-titration study, sponsored by Sarepta Therapeutics, is designed to assess the safety, tolerability, and PK of once-weekly IV infusions of SRP-4045 inadvanced-stage male patients, ages 7-21 years, with genotypically-confirmed Duchenne muscular dystrophy (DMD)characterized by deletions amenable to exon 45 skipping (e.g., exons 12-44, 18-44, 44, 46-47, 46-48, 46-49, 46-51, 46-53, or 46-55). This study will evaluate four ascending dose levels of SRP-4045 (4, 10, 20, and 30 mg/kg administered weekly for a minimum of 2 weeks per level) compared to placebo over approximately 12 weeks of a double-blind dose-titration period. The double-blind dose-titration period will be followed by an open-label extension period evaluating the safety and efficacy of SRP-4045 at 30 mg/kg (or the highest tolerated dose as determined during the dose titration) administered weekly through Week 120.


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) (Protocol B5161002)

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

This is a 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


A multicenter, open-label extension study to evaluate the long term safety of PF-06252616 in boys with Duchenne Muscular Dystrophy  (Protocol B5161004)

Johns Hopkins IRB Protocol Number:  IRB00110715
Principal Investigator:  Kathryn Wagner, M.D., Ph.D.
Status:  Active, recruiting

This study, an open-label extension (OLE) to Protocol B5161002,  will provide an assessment of the long term safety, efficacy, pharmacodynamics (PD) and pharmacokinetics (PK) of intravenous (IV) dosing of PF-06252616 in boys with Duchenne muscular dystrophy (DMD). Participants who complete the B5161002 study  will be invited to transition  directly to the OLE study. Subjects’ results from the B5161002 study may be used as  screening data for the current study. The individual dose level selected for each subject will be based on the maximum  tolerated dose from the parent Study B5161002. Subjects will be dosed with one of three PF-06252616 dose levels: 5 mg/kg, 20 mg/kg or 40 mg/kg.

Related Link: -  NCT02907619


A Phase 1b/2, Open-Label, Multiple Ascending Dose Study to Evaluate the Safety, Tolerability, Efficacy, Pharmacokinetics and Pharmacodynamics of PF-06252616 in Ambulatory Participants with LGMD2I

Johns Hopkins IRB Protocol Number:  IRB00089732
Principal Investigator:  Kathryn Wagner, M.D., Ph.D.
Status:  Active, recruiting

This is a Phase 1b/2, open-label multiple ascending dose study to evaluate the safety, tolerability PK and PD of PF-06252616 administered to ambulatory participants diagnosed with LGM2I.  The study drug is a a humanized anti myostatin monoclonal antibody that neutralizes myostatin (one of the main factors that prevents muscle growth). Three IV infused dose levels administered every 28 days will be investigated in a dose escalating fashion, 5 mg/kg, 20 mg/kg or 40 mg/kg. Approximately 20 eligible subjects will be consecutively assigned to 1 of 3 cohorts for approximately 96 weeks (cohort 1) or 64 weeks (cohorts 2 and 3). At each dose level, subjects will be followed for an initial approximate 16-week lead-in period to establish individual change in disease progression.

Related Link: -  NCT02841267


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.
S tatus : 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


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 .


An open label, expanded access program intended to provide treatment with MP-104 (deflazacort) to U.S. children, adolescents, and/or adults with Duchenne muscular dystrophy

Johns Hopkins IRB Protocol Number:  NA_00019985
Principal Investigator:  Kathryn Wagner MD, PhD
Status:  Active, not recruiting

This is an open-label, expanded access program (EAP). Approximately 1,500 patients with a confirmed diagnosis of DMD are expected to enroll in this multicenter study. Patients deemed eligible by the treating physician will be provided with deflazacort, through a specialty pharmacy. Deflazacort will be supplied free of charge and shipped directly to patients. Treating physicians will continue to follow their standard of care activities and procedures for management of DMD; costs for such activities and procedures will not be reimbursed by the sponsor. Treatment will continue until such time that deflazacort becomes commercially available in the U.S., up to three years or the program is terminated, whichever is earlier.

Related Link: – NCT02592941


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.


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.