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 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, 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: ClinicalTrials.gov - NCT02515669


An Open-Label Extension Study of the Long-Term Safety, Tolerability, and Efficacy of Drisapersen in Subjects with Duchenne Muscular Dystrophy  (BMN-051-302)

Johns Hopkins IRB Protocol Number: IRB00079299
Principal Investigator: Kathryn Wagner, M.D., Ph.D.
Status: Active, not recruiting

This phase 3b, multicenter, open-label, uncontrolled extension study, sponsored by Biomarin Pharmaceutical, Inc, aims to enroll up to 220 male subjects with DMD who have previously been treated with drisapersen. The primary dosing arm is drisapersen 6mg/kg as subcutaneous (SC) injection once a week. All subjects starting with SC injections will receive a loading dose of twice weekly 6mg/kg drisapersen for the first three weeks of treatment. This study does not have a minimum duration of participation. For subjects who have previously experienced significant safety or tolerability issues or who experience these during this study, there is the potential of an alternate intermittent dosing arm (6mg/kg/week for 8 weeks floolowed by 4 weeks of no dosing). For subjects who have previously experienced significant injection site reactions in an earlier drisapersen study, or experience similar reactions during the study, there is the potential to be dose intravenously (maximum exposure of 6mg/kg/week over a 2 hour infusion time).


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.


An Open-Label, Intrapatient Dose Escalation Study to Evaluate the Safety, Tolerability, Immunogenicity, and Biological Activity of ATYR1940 in Patients with Limb Girdle and Facioscapulohumeral Muscular Dystrophies (ATYR1904-C-004)

Johns Hopkins IRB Protocol Number: IRB00074941
Principal Investigator: Kathryn Wagner, M.D., Ph.D.
Status: Active, recruiting

This is a multinational, multicenter, open-label, intrapatient dose-escalation study designed to evaluate the safety, tolerability, immunogenicity, and biological activity of weekly and biweekly IV infusions of in patients with LGMD2B and FSHD. ATYR1940 may have a role in modulating immune responses in skeletal muscle, and the potential of ATYR1940 to therapeutically suppress inflammatory cell infiltration into skeletal muscles.

Three dose levels of ATYR1940 will be evaluated using intrapatient dose escalation: 0.3, 1.0, and 3.0 mg/kg. Up to 16 patients are planned to be enrolled, including up to 8 each with LGMD2B and FSHD.

Patients will be assigned to one of 2 treatment groups, which differ based on the maximum ATYR1940 dose level to be administered: Group A will include 4 patients with FSHD; Group B will include 4 patients with FSHD and up to 8 patients with LGMD2B. Enrollment into Groups A and B will be initiated concurrently; however, enrollment of FSHD patients into Group A must be completed before any patients with FSHD may be enrolled into Group B.

The total treatment period in this study will not exceed 13 weeks, including 1 dose of placebo at Week 1 followed by 12 weeks of dosing of ATYR1940. The dose level in this study will not exceed 3.0 mg/kg.

During the treatment period, patients will visit the study center weekly for the first 9 weeks, and biweekly for the next 4 weeks, for dosing and assessments of safety, immunogenicity, and biological and PD activity.


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: ClinicalTrials.gov - 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, not 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: ClinicalTrials.gov - 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: ClinicalTrials.gov - 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: ClinicalTrials.gov – 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.


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: ClinicalTrials.gov - NCT02312011


FOR MORE INFORMATION

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


LABORATORY RESEARCH:

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.


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.


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.

"In My Mind" Artwork Exhibit

A collection of artwork by individuals with Duchenne muscular dystrophy representing a wide array of interests, techniques, styles, and perspectives.

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