Genethon's experimental gene therapy, GNT0004, is showing promising results in an ongoing Phase 1/2/3 clinical trial for Duchenne muscular dystrophy (DMD). The data, presented at the ASGCT Breakthroughs in Muscular Dystrophy conference, indicate stable or improved motor function in patients treated with the therapy. These findings pave the way for a Phase 3 trial planned for the U.S. and Europe, potentially leading to regulatory approvals.
Mechanism of Action
DMD results from mutations in the dystrophin gene, leading to progressive muscle weakness and wasting. GNT0004 aims to deliver a gene encoding microdystrophin, a functional, shortened version of the dystrophin protein, directly to muscle cells via intravenous injection. This one-time therapy seeks to address the underlying genetic defect and improve muscle function.
Phase 1/2 Trial Results
The Phase 1/2 portion of the trial involved boys aged 6 to 10 with DMD who were still able to walk. Five patients received GNT0004, with two receiving a lower dose and three a higher dose. The higher dose will be used in the upcoming Phase 3 trial. According to Frederic Revah, PhD, CEO of Genethon, the selected dose is lower than those used in other DMD gene therapy trials.
Results from the higher-dose cohort showed that an average of 54% of muscle fibers expressed microdystrophin protein eight weeks after treatment. Furthermore, creatine phosphokinase levels, a marker of muscle damage, decreased by an average of 74% at 12 weeks post-treatment and remained low for up to 18 months in the two higher-dose patients evaluated at that time. Motor function remained stable in these three patients one to two years post-treatment, with one patient showing notable improvements. This is particularly significant, as DMD typically leads to a gradual decline in motor abilities without intervention.
Planned Phase 3 Trial
Genethon is preparing to launch a Phase 3 pivotal trial involving over 60 children in Europe in the second quarter of 2025, followed by the U.S. If the Phase 3 results are positive, Genethon intends to use the trial data to support regulatory applications for GNT0004.
Addressing AAV Antibody Challenges
Genethon is also addressing challenges related to pre-existing anti-AAV antibodies, which can prevent gene therapies from working. In partnership with Hansa Biopharma, a Phase 2 trial will evaluate imlifidase, an antibody-cleaving enzyme, in Crigler-Najjar syndrome patients with AAV neutralizing antibodies. Patients will receive imlifidase before GNT0003 gene therapy.
AI-Driven Capsid Development
Genethon scientists are also employing artificial intelligence (AI) to design a new generation of capsids for gene therapy vectors, as detailed in a recent Nature Communications article. This innovative approach aims to improve the delivery and efficacy of gene therapies for muscle diseases.
