Gene Therapy for Duchenne Muscular Dystrophy

Age: < 18

Sex: Male

Trial Phase: Phase 1 & 2

Sponsor: Megan Waldrop

Must be taking: Corticosteroids

Disqualifiers: Cardiomyopathy, HIV, Hepatitis, Autoimmune, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 1 day

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new gene therapy treatment called scAAV9.U7.ACCA for boys with Duchenne muscular dystrophy who have a specific genetic change known as duplication of exon 2. The goal is to determine if a single dose of the treatment, administered through a vein in the arm or leg, can improve muscle function. The trial seeks boys who can walk at least 10 meters without assistance or have not yet started walking and have been on stable steroid treatment if they are 4 years or older. As a Phase 1, Phase 2 trial, this research aims to understand how the treatment works in people and to measure its effectiveness in an initial, smaller group.

Will I have to stop taking my current medications?

The trial requires that participants age 4 and above must be on a stable dose and regimen of corticosteroid therapy (like prednisone or deflazacort) for at least 12 weeks before the gene transfer. Other medications may need to be stopped if they pose unnecessary risks for the gene transfer, but the protocol does not specify which ones.

Is there any evidence suggesting that scAAV9.U7.ACCA is likely to be safe for humans?

Research has shown that the scAAV9.U7.ACCA treatment has promising safety results from earlier studies. For example, tests on mice and monkeys revealed no harmful effects. These findings suggest the treatment might be safe for humans. Additionally, the treatment uses a well-studied method in gene therapy, which enhances its safety profile. However, since this is an early-phase trial, further research is needed to confirm these findings in humans. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for Duchenne Muscular Dystrophy, which often include corticosteroids and supportive therapies, scAAV9.U7.ACCA offers a groundbreaking approach by using gene therapy to address the root cause of the disease. This treatment utilizes a viral vector to deliver a modified gene designed to help produce functional dystrophin, a protein that's lacking in individuals with this condition. Researchers are excited about this therapy because it targets the genetic defect directly, potentially offering a long-term solution rather than just managing symptoms.

What evidence suggests that scAAV9.U7.ACCA might be an effective treatment for Duchenne muscular dystrophy?

Research has shown that the scAAV9.U7.ACCA gene therapy, which participants in this trial will receive, could help treat Duchenne muscular dystrophy (DMD) by addressing a specific genetic problem. Studies in mice demonstrated that this therapy can improve or even prevent DMD symptoms. It skips over a duplicated part of the gene responsible for DMD, enabling the body to produce dystrophin, an essential protein for muscles. Long-term research found that this approach leads to continuous dystrophin production, crucial for muscle health. These encouraging results suggest that scAAV9.U7.ACCA could effectively treat people with this particular genetic condition. ^{1 2 3 6 7}

Who Is on the Research Team?

Megan Waldrop, MD

Principal Investigator

Nationwide Children's Hospital

Are You a Good Fit for This Trial?

This trial is for boys aged 6 months to less than 14 years with Duchenne muscular dystrophy due to a specific genetic change (duplication of exon 2). Participants can be walking or not and must have been on stable corticosteroid therapy if over age 4. They cannot join if they have heart problems, certain infections like HIV or hepatitis, autoimmune diseases, abnormal blood counts, or high antibodies against the treatment vector.

Inclusion Criteria

I am between 6 months and 14 years old.

My test shows a specific genetic change in the DMD gene.

I can walk 10 meters without help or I cannot walk yet.

Exclusion Criteria

Your test results are outside the healthy range according to the Nationwide Children's Hospital Laboratory.

You have high levels of AAV9 binding antibodies in your blood.

Your white blood cell count is too low or too high, or your neutrophil count is too low.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a single dose of scAAV9.U7.ACCA via peripheral limb vein injection

1 day

Follow-up

Participants are monitored for safety and preliminary efficacy data

2 years

What Are the Treatments Tested in This Trial?

Interventions

• scAAV9.U7.ACCA

Trial Overview The trial tests a single dose of gene therapy called scAAV9.U7.ACCA delivered through an injection into a vein in the arm. It's designed for boys with Duchenne muscular dystrophy who have duplication of exon 2 in their genes. The study is open-label, meaning everyone knows what treatment is being given.

How Is the Trial Designed?

Group I: Cohort 1 (Minimal Efficacious Dose) Experimental Treatment 1 Intervention

The Minimal Effective Dose (MED) will be delivered.

Who Is Running the Clinical Trial?

Megan Waldrop

Lead Sponsor

Trials

2

Recruited

10+

Astellas Pharma Inc

Industry Sponsor

Trials

700

Recruited

236,000+

Headquarters

Tokyo, Japan

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Tadaaki Taniguchi

Astellas Pharma Inc

Chief Medical Officer since 2023

MD, PhD

Naoki Okamura

Astellas Pharma Inc

Chief Executive Officer since 2023

University of Tokyo, Faculty of Pharmacy

Audentes Therapeutics

Industry Sponsor

Trials

8

Recruited

270+

Published Research Related to This Trial

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]

Duchenne muscular dystrophy (DMD) is a severe genetic disorder primarily affecting boys, leading to muscle degeneration and early death, highlighting the urgent need for effective treatments.

AAV-based gene therapy using shortened microdystrophin genes shows promise as a treatment for DMD, and the article advocates for using microdystrophin expression as a surrogate endpoint to facilitate accelerated approval in clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Microdystrophin Expression as a Surrogate Endpoint for Duchenne Muscular Dystrophy Clinical Trials. Chamberlain, JS., Robb, M., Braun, S., et al.[2023]

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 study successfully demonstrated that regional vascular delivery of rAAV8 and rAAV6 carrying micro-dystrophin significantly improved muscle transduction efficiency in mdx mice, achieving over 89% transduction after three months, which is crucial for potential gene therapy in Duchenne muscular dystrophy (DMD).

The promising results in mice were translated to non-human primates, showing effective gene expression in multiple muscles, indicating that this delivery method could be adapted for clinical trials in children with DMD, enhancing the safety and efficacy of gene therapy approaches.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A translational approach for limb vascular delivery of the micro-dystrophin gene without high volume or high pressure for treatment of Duchenne muscular dystrophy. Rodino-Klapac, LR., Janssen, PM., Montgomery, CL., et al.[2018]

Gene therapy using adeno-associated virus (rAAV) to deliver mini/micro-dystrophin shows promise for treating Duchenne Muscular Dystrophy (DMD), but high doses of rAAV can lead to immune responses and liver toxicity, especially in older patients.

Research suggests that using utrophin, a protein similar to dystrophin, along with a novel MyoAAV delivery system, could enhance therapeutic effects while reducing the required rAAV dose, potentially making gene therapy safer and more effective for a broader range of patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Strategies for Bottlenecks of rAAV-Mediated Expression in Skeletal and Cardiac Muscle of Duchenne Muscular Dystrophy. Li, N., Song, Y.[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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04240314

AAV9 U7snRNA Gene Therapy to Treat Boys With DMD ... The proposed clinical trial is a systemic (intravenous) delivery of scAAV9.U7.ACCA for DMD patients with a duplication of exon 2 in the DMD gene.

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9356240/

Systemic delivery of an AAV9 exon-skipping vector ... Systemic delivery of an AAV9 exon-skipping vector significantly improves or prevents features of Duchenne muscular dystrophy in the Dup2 mouse.

3. parentprojectmd.org parentprojectmd.org/clinical-trial/aav9-u7snrna-gene-therapy-to-treat-boys-with-dmd-exon-2-duplications/

AAV9 U7snRNA Gene Therapy to Treat Boys With DMD ... The study is designed as an open-label trial to assess safety and obtain preliminary efficacy data. scAAV9.U7.ACCA will be delivered to the systemic circulation ...

4. sciencedirect.com sciencedirect.com/science/article/pii/S2329050123001833

Persistence of exon 2 skipping and dystrophin expression ... Together, these data define the long-term efficacy of scAAV9.U7.ACCA, suggesting it as a therapy for the treatment of DMD patients with exon 2 duplications.

5. cell.com cell.com/molecular-therapy-family/methods/fulltext/S2329-0501(23)00199-7

Long-term dystrophin restoration supports development of ... These data demonstrate that therapy with scAAV9.U7.ACCA to induce Dmd exon 2 skipping promotes the long-term expression of relatively high ...

6. parentprojectmd.org parentprojectmd.org/drug-development-pipeline/scaav9-u7-acca/

scAAV9.U7.ACCA ACCA, an exon skipping gene therapy candidate for patients with a duplication of exon 2 in the DMD gene. AAV functions as a delivery vehicle to introduce a DNA ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10112461/

Lack of Toxicity in Nonhuman Primates Receiving Clinically ... We have previously shown that delivery of this vector (scAAV9.U7.ACCA) to the Dup2 mouse model results in expression of full-length dystrophin from wild-type ...