Gene Transfer with SRP-6004 for Limb-Girdle Muscular Dystrophy

Age: 18 - 65

Sex: Any

Trial Phase: Phase 1

Sponsor: Sarepta Therapeutics, Inc.

Must not be taking: Gene therapy, Investigational drugs

Disqualifiers: Significant illness, Chronic drug treatment, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 1

Duration: 1 day

2 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, if you require chronic drug treatment that the investigator believes poses a risk for gene transfer, it might be a concern.

What data supports the effectiveness of the treatment SRP-6004 for Limb-Girdle Muscular Dystrophy?

Research on a similar treatment, SRP-9005, showed that gene transfer therapy in mice with a similar condition led to improvements in muscle function and structure, suggesting potential benefits for SRP-6004 in humans. ^{1 2 3 4 5}

Is SRP-6004 gene therapy safe for humans?

Research on similar gene therapies using adeno-associated virus (AAV) vectors, like those for other muscular dystrophies, shows they are generally well-tolerated with no significant toxicity observed in animal studies. However, there are concerns about immune responses, so safety measures are important to minimize risks. ^{1 6 7 8 9}

How does the treatment SRP-6004 differ from other treatments for limb-girdle muscular dystrophy?

SRP-6004 is unique because it uses gene transfer therapy to deliver a functional version of the γ-sarcoglycan gene directly into muscle cells, aiming to correct the underlying genetic defect causing limb-girdle muscular dystrophy. This approach is different from traditional treatments as it targets the root cause of the disease rather than just managing symptoms. ^{1 2 5 10 11}

What is the purpose of this trial?

This trial is testing the safety of a medicine called SRP-6004, given through a vein, in people who can walk but have a specific type of muscular dystrophy (LGMD2B/R2).

Research Team

Medical Director

Principal Investigator

Sarepta Therapeutics, Inc.

Eligibility Criteria

This trial is for ambulatory individuals with Limb Girdle Muscular Dystrophy, Type 2B/R2. Participants must have specific genetic mutations related to the condition, be able to perform motor tests, and not have high levels of certain antibodies. They can't join if they've had recent gene therapy or other investigational treatments, significant health issues, or need chronic drug treatment that could pose risks.

Inclusion Criteria

I have specific genetic mutations in the DYSF gene.

My arm and leg muscles are suitable for biopsy.

I can participate in tests that measure my muscle movements.

Exclusion Criteria

Presence of any other clinically significant illness, medical condition, or requirement for chronic drug treatment that in the opinion of the Investigator creates unnecessary risk for gene transfer.

Abnormality in protocol-specified diagnostic evaluations or laboratory tests.

Exposure to gene therapy, investigational medication, or other protocol-specified treatment within the protocol specified time limits.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a single IV infusion of SRP-6004 on Day 1

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 weeks

Treatment Details

Interventions

• SRP-6004

Trial Overview The study is testing SRP-6004's safety when given through an IV infusion to people who can walk but have LGMD2B/R2. It aims to understand how well participants tolerate this potential new treatment and its effectiveness in treating their muscular dystrophy.

Participant Groups

Group I: SRP-6004 Experimental Treatment 1 Intervention

Participants will receive single IV infusion of SRP-6004 on Day 1.

Who Is Running the Clinical Trial?

Sarepta Therapeutics, Inc.

Lead Sponsor

Trials

54

Recruited

34,000+

Findings from Research

Thigh muscle fat replacement measured by proton density fat fraction (PDFF) using MRI is a sensitive indicator of disease progression in patients with limb-girdle muscular dystrophy autosomal recessive type 12 (LGMDR12), particularly in those with intermediate-stage fat replacement, showing significant changes within just one year.

Biodex isometric dynamometry effectively captures the decline in muscle strength over one year in LGMDR12 patients, making it a valuable outcome measure for future clinical trials, while traditional clinical measures like the 6-minute walk distance and 10-meter walk test were less effective in detecting changes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prospective Natural History Study in 24 Adult Patients With LGMDR12 Over 2 Years of Follow-up: Quantitative MRI and Clinical Outcome Measures. De Wel, B., Huysmans, L., Peeters, R., et al.[2023]

This study identified a new genetic locus for limb-girdle muscular dystrophy (LGMD) on chromosome 2p, specifically linked to markers D2S134 and D2S136, after excluding other known loci.

The affected individuals from two large inbred families exhibited similar symptoms, with muscle weakness starting in the pelvic girdle during late adolescence and a generally slow progression of the disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A gene for autosomal recessive limb-girdle muscular dystrophy maps to chromosome 2p. Bashir, R., Strachan, T., Keers, S., et al.[2022]

The study developed a human codon-optimized version of microutrophin (µUtrn) that showed robust muscle expression and functional improvement in mdx mice, indicating its potential as a safer alternative to traditional dystrophin gene therapy for Duchenne muscular dystrophy (DMD).

Long-term administration of rAAV9-µUtrn resulted in lower immunogenicity and no adverse effects in toxicity studies, supporting its safety for clinical development as a gene therapy for DMD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Therapeutic potential of highly functional codon-optimized microutrophin for muscle-specific expression. Starikova, AV., Skopenkova, VV., Polikarpova, AV., et al.[2022]

AAV9-mediated delivery of the human BVES gene significantly improved muscle function and cardiac health in BVES-knockout mice, demonstrating its potential as a gene therapy for limb-girdle muscular dystrophy type R25 (LGMDR25).

The treatment showed efficacy in both neonatal and adult mice, enhancing body weight, muscle mass, and exercise performance without any observed toxicity, suggesting a promising therapeutic approach for this currently untreatable condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Systemic AAV9.BVES delivery ameliorates muscular dystrophy in a mouse model of LGMDR25. Li, H., Wang, P., Hsu, E., et al.[2023]

Gene therapy is showing promising progress in treating limb-girdle muscular dystrophies (LGMDs), particularly in conditions like calpainopathies, dysferlinopathies, and sarcoglycanopathies, with early clinical trials demonstrating safety and efficacy.

Emerging technologies such as CRISPR/Cas9 may further enhance the effectiveness of gene therapy for LGMDs, paving the way for more advanced treatment options in the future.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Unmet needs and evolving treatment for limb girdle muscular dystrophies. Pozsgai, E., Griffin, D., Potter, R., et al.[2022]

A single injection of a recombinant adeno-associated virus (AAV) vector into the tibialis anterior muscle of dystrophic hamsters resulted in over 97% recovery of muscle strength and nearly complete restoration of physiological function, indicating high efficacy of this gene therapy approach for Limb Girdle Muscular Dystrophy (LGMD) 2F.

The treatment not only improved muscle strength but also prevented pathological changes, such as muscle hypertrophy, and led to normal muscle weight and size, showcasing the potential of AAV-mediated gene therapy for long-term benefits in LGMD patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Full functional rescue of a complete muscle (TA) in dystrophic hamsters by adeno-associated virus vector-directed gene therapy. Xiao, X., Li, J., Tsao, YP., et al.[2019]

References

1. United States pubmed.ncbi.nlm.nih.gov

Systemic γ-sarcoglycan AAV gene transfer results in dose-dependent correction of muscle deficits in the LGMD 2C/R5 mouse model. [2023]

2. United States pubmed.ncbi.nlm.nih.gov

Prospective Natural History Study in 24 Adult Patients With LGMDR12 Over 2 Years of Follow-up: Quantitative MRI and Clinical Outcome Measures. [2023]

3. Switzerland pubmed.ncbi.nlm.nih.gov

Novel Variants of ANO5 in Two Patients With Limb Girdle Muscular Dystrophy: Case Report. [2022]

4. England pubmed.ncbi.nlm.nih.gov

Limb-girdle muscular dystrophies - international collaborations for translational research. [2022]

5. England pubmed.ncbi.nlm.nih.gov

A gene for autosomal recessive limb-girdle muscular dystrophy maps to chromosome 2p. [2022]

6. England pubmed.ncbi.nlm.nih.gov

Therapeutic potential of highly functional codon-optimized microutrophin for muscle-specific expression. [2022]

7. United States pubmed.ncbi.nlm.nih.gov

Systemic AAV9.BVES delivery ameliorates muscular dystrophy in a mouse model of LGMDR25. [2023]

8. France pubmed.ncbi.nlm.nih.gov

Gene therapy for primary myopathies: literature review and prospects. [2023]

9. England pubmed.ncbi.nlm.nih.gov

Unmet needs and evolving treatment for limb girdle muscular dystrophies. [2022]

10. United States pubmed.ncbi.nlm.nih.gov

Safety and efficacy of AAV-mediated calpain 3 gene transfer in a mouse model of limb-girdle muscular dystrophy type 2A. [2012]

11. United States pubmed.ncbi.nlm.nih.gov

Full functional rescue of a complete muscle (TA) in dystrophic hamsters by adeno-associated virus vector-directed gene therapy. [2019]