Gene Therapy GNT0004 Demonstrates Early Efficacy, Safety in Duchenne Muscular Dystrophy


Although a small sample of 5 patients with DMD, results showed significant expression of microdystrophin and reductions in creatine kinase, a biomarker of muscular distress, in GTN0004-treated patients.

Francesco Muntoni, chair of pediatric neurology in the Developmental Neurosciences Department at the Queen Square Center for Neuromuscular Diseases

Francesco Muntoni, MD

Data from an early-stage trial showed that treatment with GNT0004 (Genethon), an investigational adeno-associated virus (AAV8) vector-based gene therapy, was safe and well tolerated among patients with Duchenne muscular dystrophy (DMD), with encouraging results on microdystrophin expression and functional improvement. Based on the recommendation from an independent expert committee, Genethon is preparing the pivotal part of the clinical trial in the EU.

The trial is unique in that it combines phases 1, 2, and 3 with a dose-escalation phase, followed by a pivotal phase at the selected dose. To date, 5 ambulant boys aged between 6 and 10 have been treated with GNT0004, with 2 receiving only the first dose and 3 receiving the second as well. Presented at Myology 2024 international scientific conference, held in Paris, France, GT0004 was assessed a dosage of 3 x 1013 v/kg (second dose level) in combination with transient immunological prophylactic treatment.

All told, after 8 weeks of treatment, up to 85% of muscle fibers expressed microdystrophin (mean, 54%; 15%-85%), as measured by immunohistochemistry, and demonstrated reconstitution of the dystrophin-associated protein complex. This expression coincided with a significant number of vector genome copies/muscle fiber nuclei, up to 2.4 (mean 1.2; 0.4-2.4). Notably, the dosage level used in this study was lower than those used in other gene therapy trials 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, patients on the therapy also saw a decrease in creatine phosphokinase (CPK) levels. After 12 weeks of treatment, there was an attenuation between 50% and 87% (mean: 74%) in CPK levels. CPK, also known as creatine kinase, is an enzyme found in the heart, brain, and skeletal muscles that helps produce energy and is important for muscle function.

READ MORE: Final Readout of FIREFISH Study Showcases Risdiplam’s Pronounced Effects in Spinal Muscular Atrophy

For 1 patient in cohort 2 who had 1-year efficacy results available, treatment with GNT0004 resulted in a positive clinical evolution, demonstrated through scores on the North Star Ambulatory Assessment. Other assessments, such as 10 Meter Walk Test and ability to stand up, also revealed a positive trend with treatment.

DMD, the most prevalent form of muscular dystrophy, is a genetic disorder stemming from mutations in the dystrophin gene. Dystrophin deficiency leads to plasma-membrane instability, causing myofiber necrosis and muscle weakness. The absence of dystrophin disrupts the contraction machinery, and the continuous degeneration/regeneration cycles in dystrophic muscles lead to persistent muscular injury and inhibition of regenerative potential caused by the depletion of satellite cells.2

In recent years, gene therapy, exon skipping machinery, and the transplantation of autologous genetically corrected stem cells have emerged as potential approaches for DMD, although with contradictory outcomes. To date, Sarepta Therapeutics’ SRP-9001 (Elevidys), otherwise known as delandistrogene moxeparvovec, is the only approved gene therapy for patients with DMD. The agent, approved under the accelerated approval pathway in June 2023, is an AAV vector-based gene therapy, indicated for ambulatory pediatric patients aged 4 to 5 years with DMD.3

1. First clinical trial results of gene therapy (GNT0004) for Duchenne muscular dystrophy presented at international Myology 2024 Congress. News release. Genethon. April 23, 2024. Accessed June 11, 2024.
2. Molinaro M, Torrente Y, Villa C, Farini A. Advancing biomarker discovery and therapeutic targets in Duchenne muscular dystrophy: a comprehensive review. Int J Mol Sci. 2024;25(1):631. doi:10.3390/ijms25010631
3. Sarepta Therapeutics announces FDA approval of Elevidys, the first gene therapy to treat Duchenne muscular dystrophy. News release. June 22, 2023. Accessed June 11, 2024.
Recent Videos
Martin Tolar, MD, PhD
Patricia K. Coyle, MD
Aliza Ben-Zacharia, PhD, DNP, ANP-BC, FAAN
4 KOLs are featured in this series.
4 KOLs are featured in this series.
4 KOLs are featured in this series.
4 KOLs are featured in this series.
5 KOLs are featured in this series.
5 KOLs are featured in this series.
Martin Tolar, MD, PhD
© 2024 MJH Life Sciences

All rights reserved.