Gene Therapy for Limb-Girdle Muscular Dystrophy
(EMERGENE Trial)
Recruiting in Palo Alto (17 mi)
+4 other locations
Age: Any Age
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 3
Waitlist Available
Sponsor: Sarepta Therapeutics, Inc.
No Placebo Group
Pivotal Trial (Near Approval)
Prior Safety Data
Trial Summary
What is the purpose of this trial?This is a multicenter, global study of the effects of a single systemic dose of SRP-9003 on beta-sarcoglycan (β-SG) gene expression in participants with limb-girdle muscular dystrophy, type 2E/R4 (LGMD2E/R4). This study will consist of both ambulatory participants (Cohort 1) and non-ambulatory participants (Cohort 2).
Do I need to stop my current medications to join the trial?
The trial protocol does not specify if you need to stop your current medications. However, if you are on active immunosuppressant treatment for an autoimmune disease, you may be excluded from the trial.
What data supports the idea that Gene Therapy for Limb-Girdle Muscular Dystrophy (also known as: Bidridistrogene Xeboparvovec (SRP-9003), SRP-9003) is an effective treatment?
The available research shows that gene therapy using AAV9.BVES significantly improved muscle mass, strength, and exercise performance in a mouse model of Limb-Girdle Muscular Dystrophy type R25. It also normalized heart rate under stress and showed no obvious toxicity. This suggests that gene therapy can effectively improve symptoms of muscular dystrophy. While the research primarily focuses on animal models, these results provide promising evidence for the potential effectiveness of gene therapy in treating this condition.
12345What safety data exists for gene therapy in treating Limb-Girdle Muscular Dystrophy?
The safety data for delandistrogene moxeparvovec (SRP-9001) gene therapy, primarily studied for Duchenne muscular dystrophy, indicates that the most common treatment-related adverse events were vomiting, decreased appetite, and nausea, which mostly occurred within the first 90 days and resolved. Long-term safety and functional outcomes have been evaluated, showing robust expression of the therapeutic protein and stabilization of motor function up to 2 years post-treatment. No obvious toxicity was detected in related studies, suggesting a favorable safety profile.
12367Is the treatment Bidridistrogene Xeboparvovec (SRP-9003) a promising treatment for Limb-Girdle Muscular Dystrophy?
The treatment Bidridistrogene Xeboparvovec (SRP-9003) shows promise for Limb-Girdle Muscular Dystrophy because similar gene therapies have been successful in improving muscle function and strength in other types of muscular dystrophy. These therapies use a virus to deliver a helpful gene to muscle cells, which can lead to better muscle performance and overall health.
12467Eligibility Criteria
This trial is for people with a muscle condition called Limb Girdle Muscular Dystrophy 2E/R4. It's open to those who can move around on their own (Cohort 1) and those who cannot (Cohort 2). Specific eligibility details are not provided, but typically participants must meet certain health criteria.Inclusion Criteria
I can walk without help and do so quickly.
Cohort 2, only non-ambulatory participants: 10MWT ≥30 seconds or unable to perform, PUL 2.0 entry scale score ≥3, Participants must possess 1 homozygous or 2 heterozygous pathogenic and/or likely pathogenic β-SG DNA gene mutations, Able to cooperate with muscle testing, Participants must have adeno-associated virus serotype rh74 (AAVrh74) antibody titers <1:400 (that is, not elevated) as determined by AAVrh74 antibody enzyme-linked immunosorbent assay.
Exclusion Criteria
Left ventricular ejection fraction < 40% or clinical signs and/or symptoms of cardiomyopathy, Forced vital capacity ≤40% of predicted value and/or requirement for nocturnal ventilation, Diagnosis of (or ongoing treatment for) an autoimmune disease and on active immunosuppressant treatment, Presence of any other clinically significant illness or medical condition (other than LGMD2E/R4)
Participant Groups
The study tests an experimental gene therapy named Bidridistrogene Xeboparvovec (SRP-9003), which aims to correct the genetic defect causing the disease. Participants will receive one dose of this therapy, and its effects on gene expression will be monitored.
1Treatment groups
Experimental Treatment
Group I: SRP-9003Experimental Treatment2 Interventions
Participants will receive a single intravenous (IV) infusion of SRP-9003.
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
University of California, San Diego-Altman Clinical and Translational Research InstituteLa Jolla, CA
Nationwide Childrens HospitalColumbus, OH
The Children's Hospital of PhiladelphiaPhiladelphia, PA
Children's Hospital of The King's DaughterNorfolk, VA
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Who Is Running the Clinical Trial?
Sarepta Therapeutics, Inc.Lead Sponsor
References
Systemic AAV9.BVES delivery ameliorates muscular dystrophy in a mouse model of LGMDR25. [2023]Limb-girdle muscular dystrophy type R25 (LGMDR25) is caused by recessive mutations in BVES encoding a cAMP-binding protein, characterized by progressive muscular dystrophy with deteriorating muscle function and impaired cardiac conduction in patients. There is currently no therapeutic treatment for LGMDR25 patients. Here we report the efficacy and safety of recombinant adeno-associated virus 9 (AAV9)-mediated systemic delivery of human BVES driven by a muscle-specific promoter MHCK7 (AAV9.BVES) in BVES-knockout (BVES-KO) mice. AAV9.BVES efficiently transduced the cardiac and skeletal muscle tissues when intraperitoneally injected into neonatal BVES-KO mice. AAV9.BVES dramatically improved body weight gain, muscle mass, muscle strength, and exercise performance in BVES-KO mice regardless of sex. AAV9.BVES also significantly ameliorated the histopathological features of muscular dystrophy. The heart rate reduction was also normalized in BVES-KO mice under exercise-induced stress following systemic AAV9.BVES delivery. Moreover, intravenous AAV9.BVES administration into adult BVES-KO mice after the disease onset also resulted in substantial improvement in body weight, muscle mass, muscle contractility, and stress-induced heart rhythm abnormality. No obvious toxicity was detected. Taken together, these results provide the proof-of-concept evidence to support the AAV9.BVES gene therapy for LGMDR25.
Expression of SRP-9001 dystrophin and stabilization of motor function up to 2 years post-treatment with delandistrogene moxeparvovec gene therapy in individuals with Duchenne muscular dystrophy. [2023]Introduction: Delandistrogene moxeparvovec (SRP-9001) is an investigational gene transfer therapy designed for targeted expression of SRP-9001 dystrophin protein, a shortened dystrophin retaining key functional domains of the wild-type protein. Methods: This Phase 2, double-blind, two-part (48 weeks per part) crossover study (SRP-9001-102 [Study 102]; NCT03769116) evaluated delandistrogene moxeparvovec in patients, aged ≥4 to <8 years with Duchenne muscular dystrophy. Primary endpoints (Part 1) were change from baseline (CFBL) in SRP-9001 dystrophin expression (Week 12), by Western blot, and in North Star Ambulatory Assessment (NSAA) score (Week 48). Safety assessments included treatment-related adverse events (TRAEs). Patients were randomized and stratified by age to placebo (n = 21) or delandistrogene moxeparvovec (n = 20) and crossed over for Part 2. Results: SRP-9001 dystrophin expression was achieved in all patients: mean CFBL to Week 12 was 23.82% and 39.64% normal in Parts 1 and 2, respectively. In Part 1, CFBL to Week 48 in NSAA score (least-squares mean, LSM [standard error]) was +1.7 (0.6) with treatment versus +0.9 (0.6) for placebo; p = 0.37. Disparity in baseline motor function between groups likely confounded these results. In 4- to 5-year-olds with matched baseline motor function, CFBL to Week 48 in NSAA scores was significantly different (+2.5 points; p = 0.0172), but not significantly different in 6-to-7-year-olds with imbalanced baseline motor function (-0.7 points; p = 0.5384). For patients treated with delandistrogene moxeparvovec in Part 2, CFBL to Week 48 in NSAA score was +1.3 (2.7), whereas for those treated in Part 1, NSAA scores were maintained. As all patients in Part 2 were exposed to treatment, results were compared with a propensity-score-weighted external control (EC) cohort. The LSM difference in NSAA score between the Part 2 treated group and EC cohort was statistically significant (+2.0 points; p = 0.0009). The most common TRAEs were vomiting, decreased appetite, and nausea. Most occurred within the first 90 days and all resolved. Discussion: Results indicate robust expression of SRP-9001 dystrophin and overall stabilization in NSAA up to 2 years post-treatment. Differences in NSAA between groups in Part 1 were not significant for the overall population, likely because cohorts were stratified only by age, and other critical prognostic factors were not well matched at baseline.
Evaluation of an AAV9-mini-dystrophin gene therapy candidate in a rat model of Duchenne muscular dystrophy. [2023]Duchenne muscular dystrophy (DMD) is an X-linked disease caused by loss-of-function mutations in the dystrophin gene and is characterized by muscle wasting and early mortality. Adeno-associated virus-mediated gene therapy is being investigated as a treatment for DMD. In the nonclinical study documented here, we determined the effective dose of fordadistrogene movaparvovec, a clinical candidate adeno-associated virus serotype 9 vector carrying a human mini-dystrophin transgene, after single intravenous injection in a dystrophin-deficient (DMDmdx) rat model of DMD. Overall, we found that transduction efficiency, number of muscle fibers expressing the human mini-dystrophin polypeptide, improvement of the skeletal and cardiac muscle tissue architecture, correction of muscle strength and fatigability, and improvement of diastolic and systolic cardiac function were directly correlated with the amount of vector administered. The effective dose was then tested in older DMDmdx rats with a more dystrophic phenotype similar to the pathology observed in older patients with DMD. Except for a less complete rescue of muscle function in the oldest cohort, fordadistrogene movaparvovec was also found to be therapeutically effective in older DMDmdx rats, suggesting that this product may be appropriate for evaluation in patients with DMD at all stages of disease.
Full functional rescue of a complete muscle (TA) in dystrophic hamsters by adeno-associated virus vector-directed gene therapy. [2019]Limb girdle muscular dystrophy (LGMD) 2F is caused by mutations in the delta-sarcoglycan (SG) gene. Previously, we have shown successful application of a recombinant adeno-associated virus (AAV) vector for genetic and biochemical rescue in the Bio14.6 hamster, a homologous animal model for LGMD 2F (J. Li et al., Gene Ther. 6:74-82, 1999). In this report, we show efficient and long-term delta-SG expression accompanied by nearly complete recovery of physiological function deficits after a single-dose AAV vector injection into the tibialis anterior muscle of the dystrophic hamsters. AAV vector treatment led to more than 97% recovery in muscle strength for both the specific twitch force and the specific tetanic force, when compared to the age-matched control. Vector treatment also prevented pathological muscle hypertrophy and resulted in normal muscle weight and size. Finally, vector-treated muscle showed substantial improvement of the histopathology. This is the first report of successful functional rescue of an entire muscle after AAV-mediated gene delivery. This report also demonstrates the feasibility of in vivo gene therapy for LGMD patients by using AAV vectors.
Long-term microdystrophin gene therapy is effective in a canine model of Duchenne muscular dystrophy. [2018]Duchenne muscular dystrophy (DMD) is an incurable X-linked muscle-wasting disease caused by mutations in the dystrophin gene. Gene therapy using highly functional microdystrophin genes and recombinant adeno-associated virus (rAAV) vectors is an attractive strategy to treat DMD. Here we show that locoregional and systemic delivery of a rAAV2/8 vector expressing a canine microdystrophin (cMD1) is effective in restoring dystrophin expression and stabilizing clinical symptoms in studies performed on a total of 12 treated golden retriever muscular dystrophy (GRMD) dogs. Locoregional delivery induces high levels of microdystrophin expression in limb musculature and significant amelioration of histological and functional parameters. Systemic intravenous administration without immunosuppression results in significant and sustained levels of microdystrophin in skeletal muscles and reduces dystrophic symptoms for over 2 years. No toxicity or adverse immune consequences of vector administration are observed. These studies indicate safety and efficacy of systemic rAAV-cMD1 delivery in a large animal model of DMD, and pave the way towards clinical trials of rAAV-microdystrophin gene therapy in DMD patients.
Delandistrogene Moxeparvovec: First Approval. [2023]Delandistrogene moxeparvovec (delandistrogene moxeparvovec-rokl; ELEVIDYS®) is an adeno-associated virus (AAV) vector-based gene therapy designed to deliver a gene encoding a micro-dystrophin protein [i.e. a shortened (138 kDa) version of the dystrophin protein expressed in normal muscle cells (427 kDa)] to all muscles involved in the pathology of Duchenne muscular dystrophy (DMD). Developed by Sarepta Therapeutics, it is the first gene therapy to be approved (in June 2023 under the Accelerated Approval pathway) for the treatment of DMD in the USA, where it is indicated for ambulatory paediatric patients aged 4 through 5 years with DMD and a confirmed mutation in the dystrophin (DMD) gene. The recommended dose of delandistrogene moxeparvovec is 1.33 × 1014 vector genomes per kg of body weight or 10 mL/kg body weight, administered as a single intravenous infusion. Delandistrogene moxeparvovec is undergoing clinical development in several countries/regions, including the EU and Japan. This article summarizes the milestones in the development of delandistrogene moxeparvovec leading to this first approval in the USA for the treatment of ambulatory paediatric patients aged 4 through 5 years with DMD and a confirmed mutation in the DMD gene.
Long-term safety and functional outcomes of delandistrogene moxeparvovec gene therapy in patients with Duchenne muscular dystrophy: A phase 1/2a nonrandomized trial. [2023]Delandistrogene moxeparvovec is indicated in the United States for the treatment of ambulatory pediatric patients aged 4 through 5 years with Duchenne muscular dystrophy (DMD) with a confirmed mutation in the DMD gene. Long-term delandistrogene moxeparvovec microdystrophin protein (a shortened dystrophin that retains key functional domains of the wild-type protein) expression may positively alter disease progression in patients with DMD. We evaluated long-term safety and functional outcomes of delandistrogene moxeparvovec in patients with DMD.