Early Trial Data Highlights Potential of Gene Therapy GNT0004 for Duchenne Muscular Dystrophy

Interim results from the ongoing, international, all-in-one GNT-016-MDYF trial indicated that GNT0004 (Genethon), an investigational gene therapy designed to target skeletal and cardiac muscles, led to sustained reductions in creatine kinase (CK) levels and stabilization or improvement in functional outcomes among young boys with Duchenne muscular dystrophy (DMD).¹

Data from Part 1 of the study, which included a dose-escalation phase, showed that patients receiving Dose 2 (3×10¹³ vg/kg) experienced a persistent 68% reduction in CK levels over 2 years, suggesting long-term stabilization of muscle integrity. Additionally, clinical measures such as the North Star Ambulatory Assessment (NSAA) and stride velocity (SV95C) demonstrated improvements compared with an external control group from a natural history study.

The trial enrolled 5 ambulatory boys with DMD, aged 6 to 10 years, who were on stable corticosteroid treatment. Three patients received Dose 2, which was ultimately selected for further evaluation in the pivotal phase 3 portion of the study. All told, muscle biopsies at week 8 showed that 53% of fibers expressed the therapeutic dystrophin variant (hMD1).

Clinically, at 1 year, patients treated with Dose 2 demonstrated a 4.7-point improvement on the NSAA scale and a 0.1 m/s increase in SV95C, indicating stabilization or enhancement of motor function compared with the expected decline seen in untreated patients. Notably, no serious adverse events were reported at this dose level, supporting its potential safety profile.

These results were recently presented by Fei Cao, medical program lead at Genethon, at the 2025 Muscular Dystrophy Association (MDA) Clinical & Scientific Conference, held March 16-19 in Dallas, Texas. With these encouraging results, Part 2 of the trial will further assess GNT0004’s efficacy in a larger, placebo-controlled cohort to confirm its clinical benefit and long-term impact.

READ MORE: Dystrophin Expressing Chimeric Cell Therapy Demonstrates Long-Term Safety in Non-Ambulatory Duchenne Muscular Dystrophy

Building on these early findings, additional data previously presented at the Myology 2024 International Scientific Conference in Paris, France, reinforced the potential of GNT0004 as a promising gene therapy for DMD. The study evaluated the second dose level (3×10¹³ vg/kg) in combination with transient immunological prophylactic treatment, demonstrating both safety and encouraging biological effects.²

At 8 weeks post-treatment, microdystrophin expression was detected in up to 85% of muscle fibers (mean: 54%; range: 15%-85%) based on immunohistochemistry, alongside reconstitution of the dystrophin-associated protein complex. This expression was supported by the presence of vector genome copies within muscle fiber nuclei (mean: 1.2; range: 0.4-2.4). Notably, the dosing regimen used in this trial was lower than that of other gene therapy studies for DMD.

Presented by principal investigator Francesco Muntoni, MD, chair of pediatric neurology in the Developmental Neurosciences Department at the Queen Square Center for Neuromuscular Diseases, reductions in creatine phosphokinase (CPK) levels were also observed, with an average decrease of 74% (range: 50%-87%) by week 12. Given CPK’s role as a key biomarker of muscle damage, this decline suggests reduced disease-related muscle breakdown.

For 1 patient in cohort 2 with available 1-year follow-up data, treatment with GNT0004 led to functional gains, as reflected by NSAA scores and improvements in measures such as the 10-Meter Walk Test and ability to stand up. These findings further support the therapy’s potential to modify disease progression, with additional confirmation expected from the next phase of clinical trials.

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REFERENCES
1. Fei Cao. GNT0004, Genethon’s AAV-based gene therapy for Duchenne muscular dystrophy: long-term data of boys enrolled in the phase I/II of GNT-016-MDYF study. Presented at: 2025 MDA Clinical & Scientific Conference; March 16-19. Dallas, TX. Abstract LB423.
2. First Clinical Trial Results of Gene Therapy (GNT0004) for Duchenne Muscular Dystrophy presented at International Myology 2024 Congress. News release. Genethon. Published April 23, 2024. Accessed March 17, 2025. https://www.genethon.com/first-clinical-trial-results-of-gene-therapy-gnt0004-for-duchenne-muscular-dystrophy-presented-at-international-myology-2024-congress/