Genethon’s Gene Therapy GNT0004 Continues to Show Potential in DMD
Patients treated at Dose 2 in the dose-escalation phase of Part 1 of the study showed a persistent 68% reduction in CK levels over 2 years.
This article originally appeared on our sister site, NeurologyLive®.
Genethon’s GNT0004, an investigational recombinant adeno-associated virus (AAV) vector-based gene therapy intended to treated Duchenne muscular dystrophy (DMD), effected sustained reductions in creatine kinase (CK) levels and stabilization or improvement in functional outcomes for young boys treated in the ongoing, international, all-in-one GNT-016-MDYF clinical trial.1 Data from the trial were presented at the 2025 Muscular Dystrophy Association (MDA) Clinical & Scientific Conference, held March 16-19 in Dallas, Texas, by Fei Cao, the medical program lead at Genethon.
Patients treated at Dose 2 (3×10¹³ vg/kg) in the dose-escalation phase of Part 1 of the study showed a persistent 68% reduction in CK levels over 2 years, indicating long-term muscle integrity stabilization. Furthermore, improvements compared to an external control group from a natural history study were seen on clinical measures such as the North Star Ambulatory Assessment (NSAA) and stride velocity (SV95C).
In total, 5 ambulatory boys with DMD, who were aged 6 to 10 years and receiving a stable corticosteroid regimen, were enrolled in the study. Among these patients, 3 were treated at Dose 2. Notably, this dose has been chosen to be utilized in the pivotal phase 3 portion of GNT-016-MDYF. Muscle biopsies, taken at 8 weeks posttreatment, demonstrated that the therapeutic dystrophin variant (hMD1) was expressed in 53% of fibers.
Patients treated with Dose 2 showed a 4.7-point improvement on the NSAA scale and a 0.1 m/s increase in SV95C at 1 year, suggesting that motor function had improved or stabilized in contrast to the decline that would be expected in untreated patients. With regard to safety, there were no serious adverse events observed in patients who were treated at Dose 2. In light of these encouraging findings, Part 2 of the study will further assess the gene therapy's efficacy in a larger, placebo-controlled cohort to confirm its clinical benefit and long-term impact.
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 a dose equivalent to Dose 2 from GNT-016-MDYF (3×10¹³ vg/kg) in combination with transient immunological prophylactic treatment, demonstrating both safety and encouraging biological effects.2
At 8 weeks posttreatment, 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 12 weeks posttreatment. 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 results, treatment with GNT0004 effected 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.
Click here for more MDA 2025 coverage.
