Gene Therapy for Limb-Girdle Muscular Dystrophy

Recruiting at 2 trial locations

Overseen By Damien Bouvier

Age: < 18

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Atamyo Therapeutics

Disqualifiers: Cardiomyopathy, Respiratory assistance, HIV, others

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

Compensation: Varies

Number of Visits: 0

6 Participants Needed

Trial Summary

What is the purpose of this trial?

The purpose of ATA-003-GSAR study is to evaluate the safety and tolerability of a single intravenous infusion of ATA-200 in pediatric patients with limb girdle muscular dystrophy type 2c/R5 (LGMD R5). Patients will be treated sequentially in 2 dose-cohorts.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. However, if you have a medical condition that might interfere with the study or are currently in another clinical trial, you may not be eligible to participate.

What data supports the effectiveness of the treatment ATA-200 for Limb-Girdle Muscular Dystrophy?

Gene therapy using adeno-associated viral vectors (AAV) has shown promise in treating various muscular dystrophies, including limb-girdle muscular dystrophies, by replacing or editing faulty genes. Studies on similar treatments for Duchenne muscular dystrophy have demonstrated improved muscle function and reduced immune response, suggesting potential effectiveness for ATA-200 in limb-girdle muscular dystrophy. ^{1 2 3 4 5}

Is gene therapy using ATA-200 or similar treatments generally safe for humans?

Gene therapy using adeno-associated virus (AAV) vectors has shown promise in treating neuromuscular disorders, but some trials have reported serious side effects. However, studies on specific gene therapies, like those for Duchenne muscular dystrophy, have shown no adverse changes in animal models, suggesting potential safety in humans. ^{4 6 7 8 9}

How is the treatment ATA-200 for limb-girdle muscular dystrophy different from other treatments?

ATA-200 is a gene therapy that uses adeno-associated viral (AAV) vectors to deliver genetic material directly to muscle cells, aiming to correct the underlying genetic defect causing limb-girdle muscular dystrophy. This approach is unique because it targets the root cause of the disease with a single dose, unlike traditional treatments that may only address symptoms. ^{1 3 5 10 11}

Eligibility Criteria

This trial is for boys and girls aged 6 to under 12 with Limb-Girdle Muscular Dystrophy type R5, who can walk 10 meters in less than 15 seconds and get up from a chair with or without help. They must have been diagnosed before age 10 based on symptoms and genetic tests.

Inclusion Criteria

I am between 6 and 11 years old and can walk.

I can walk 10 meters in under 15 seconds and get up from a chair with or without using my arms.

I was diagnosed with LGMDR5 before I turned 10.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation Treatment

Participants receive a single intravenous infusion of ATA-200 in two sequential dose cohorts with a 4-week interval between treatments

6 months

Multiple visits for safety evaluation

Follow-up

Participants are monitored for safety and effectiveness after treatment

4.5 years

Treatment Details

Interventions

• ATA-200

Trial Overview The ATA-200 gene therapy is being tested for safety and how well it's tolerated in kids with LGMDR5. It involves one dose of the therapy given through an IV. Patients are grouped into two different dose levels to see what amount is safe.

Participant Groups

Group I: Cohort 2 Experimental Treatment 1 Intervention

ATA-200 Dose level 2: 3.0E+14 vg/Kg, solution for injection, single IV infusion over 2h

Group II: Cohort 1 Experimental Treatment 1 Intervention

ATA-200 Dose level 1: 1.0E+14 vg/Kg, solution for injection, single IV infusion over 2h

Who Is Running the Clinical Trial?

Atamyo Therapeutics

Lead Sponsor

Trials

3

Recruited

100+

Findings from Research

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]

The micro-dystrophin gene transfer using rAAVrh74.MHCK7 was found to be well tolerated in a phase 1/2a trial with four young patients, showing only mild to moderate adverse events and no serious complications over one year.

All patients demonstrated significant expression of micro-dystrophin in muscle fibers and improvements in functional measures, such as North Star Ambulatory Assessment scores and reduced creatine kinase levels, indicating potential benefits beyond standard care for Duchenne muscular dystrophy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Assessment of Systemic Delivery of rAAVrh74.MHCK7.micro-dystrophin in Children With Duchenne Muscular Dystrophy: A Nonrandomized Controlled Trial. Mendell, JR., Sahenk, Z., Lehman, K., et al.[2021]

Adeno-associated viral vector (AAV)-based gene therapy is being explored as a promising treatment for various types of muscular dystrophy (MD), which currently lacks effective therapies for most patients.

Recent studies and ongoing clinical trials are focusing on different strategies using AAV, including gene replacement, gene knockdown, and gene editing, showing potential for treating conditions like Duchenne MD and myotonic dystrophy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

AAV-based gene therapies for the muscular dystrophies. Crudele, JM., Chamberlain, JS.[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]

The clinical trial demonstrated that the chimeric AAV2.5 vector is safe and well tolerated in boys with Duchenne muscular dystrophy (DMD), with no cellular immune response detected against the AAV2.5 capsid.

AAV2.5 showed effective gene transfer, with recombinant AAV genomes found in all patients, indicating its potential for efficient muscle transduction and paving the way for future gene therapy applications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1 gene therapy for Duchenne muscular dystrophy using a translational optimized AAV vector. Bowles, DE., McPhee, SW., Li, C., et al.[2022]

The Muscular Dystrophy Association (MDA) has invested over $125 million in gene therapy for neuromuscular disorders over the past 20 years, highlighting its commitment to advancing treatments in this field.

In January 2022, MDA organized a summit with experts to discuss safety challenges and adverse events related to adeno-associated virus (AAV) gene therapies, emphasizing the need for collaboration to overcome obstacles in translating these therapies from research to clinical practice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Meeting Report: 2022 Muscular Dystrophy Association Summit on 'Safety and Challenges in Gene Transfer Therapy'. Lek, A., Atas, E., Hesterlee, SE., et al.[2023]

AAV5 gene transfer successfully produced full-length dysferlin protein in dysferlin-deficient mice, correcting functional deficits in muscle repair, which is crucial for treating dysferlinopathies.

The method of intravascular regional gene transfer through the femoral artery showed high levels of targeted transduction in specific muscle groups, paving the way for future clinical trials and demonstrating the potential of AAV5 for delivering large therapeutic genes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Homologous recombination mediates functional recovery of dysferlin deficiency following AAV5 gene transfer. Grose, WE., Clark, KR., Griffin, D., et al.[2021]

A novel dual high-capacity adenovirus-adeno-associated virus (hcAd/AAV) vector has been developed to deliver the large dystrophin gene, which is crucial for treating Duchenne muscular dystrophy (DMD).

This vector successfully restored dystrophin production in muscle tissues of mdx mice and showed potential for stable gene integration in human cells, indicating its promise for safe and effective gene therapy for DMD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transfer of the full-length dystrophin-coding sequence into muscle cells by a dual high-capacity hybrid viral vector with site-specific integration ability. Gonçalves, MA., van Nierop, GP., Tijssen, MR., et al.[2018]

Recombinant adeno-associated virus vector-mediated gene transfer shows promise as a general strategy for treating neuromuscular disorders, with successful symptom rescue in animal models and ongoing clinical trials for conditions like spinal muscular atrophy (SMA) and Duchenne muscular dystrophy (DMD).

While the gene therapy trials have demonstrated promising efficacy, they have also reported serious adverse events, highlighting the need for careful monitoring and the development of safer second-generation therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Of rAAV and Men: From Genetic Neuromuscular Disorder Efficacy and Toxicity Preclinical Studies to Clinical Trials and Back. Buscara, L., Gross, DA., Daniele, N.[2023]

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]

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. England pubmed.ncbi.nlm.nih.gov

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

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

Assessment of Systemic Delivery of rAAVrh74.MHCK7.micro-dystrophin in Children With Duchenne Muscular Dystrophy: A Nonrandomized Controlled Trial. [2021]

3. England pubmed.ncbi.nlm.nih.gov

AAV-based gene therapies for the muscular dystrophies. [2022]

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

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

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

Phase 1 gene therapy for Duchenne muscular dystrophy using a translational optimized AAV vector. [2022]

6. Netherlands pubmed.ncbi.nlm.nih.gov

Meeting Report: 2022 Muscular Dystrophy Association Summit on 'Safety and Challenges in Gene Transfer Therapy'. [2023]

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

Homologous recombination mediates functional recovery of dysferlin deficiency following AAV5 gene transfer. [2021]

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

Transfer of the full-length dystrophin-coding sequence into muscle cells by a dual high-capacity hybrid viral vector with site-specific integration ability. [2018]

9. Switzerland pubmed.ncbi.nlm.nih.gov

Of rAAV and Men: From Genetic Neuromuscular Disorder Efficacy and Toxicity Preclinical Studies to Clinical Trials and Back. [2023]

10. 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]

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]