Genethon’s Duchenne Muscular Dystrophy Gene Therapy GNT0004 Produces Expression of Microdystrophin in Phase 1/2/3 Trial
For the 3 patients who were treated at the higher dose, immunohistochemistry showed that a mean of 54% of muscle fibers were expressing microdystrophin.
Genethon’s GNT0004, an investigational recombinant adeno-associated virus (AAV) vector-based gene therapy intended to treated Duchenne muscular dystrophy (DMD), has demonstrated the ability to produce expression of microdystrophin, among other signs of efficacy, in a phase 1/2/3 clinical trial.1,2 The data were presented by Francesco Muntoni, MD, the principal investigator of the trial and the chair of paediatric neurology at University College London Great Ormond Street Institute of Child Health, at the Myology 2024 International Scientific Congress, held April 22 to 25, in Paris, France.
Among 5 patients treated in the multicenter clinical trial, 2 patients received the study’s lower dose (1x1013 vg/kg) and 3 patients received the study’s higher dose (3x1013 vg/kg). For the 3 patients who were treated at the higher dose, immunohistochemistry showed that a mean of 54% of muscle fibers (range, 15% to 85%) were expressing microdystrophin, the therapeutic transgene delivered by GNT0004, at 8 weeks posttreatment. Genethon noted that alongside these expression levels, a mean of 1.2 vector genome copies per muscle fiber nuclei (range, 0.4 to 2.5) were observed. Furthermore, at 12 weeks posttreatment for these patients, levels of CPK, a biomarker for muscular destress, had been reduced by a mean of 74% (range, 50% to 87%). In the first patient who received the higher dose, the decrease was noted to be persistent at up to 18 months of follow-up. Genethon stated that this patient also showed positive trends on functional assessments at 1 year posttreatment including the North Star Ambulatory Assessment, the 10 Meter Walk Test, and ability to stand up.
“DMD is a rare, X-linked progressive disease caused by mutations in the dystrophin gene, leading to dystrophin deficiency in muscles,” Muntoni and colleagues wrote in their abstract.2 “The lack of dystrophin in myocytes results in progressive muscle degeneration that manifests primarily as muscle weakness and early death during the second or third decade of life, with the most common cause of death being cardiorespiratory failure. GNT0004 is a recombinant serotype 8 AAV vector-based gene therapy containing a shortened, but functional version of DMD gene (hMD1) optimized with key functional domains of full-length dystrophin. The hMD1 transgene is driven by aSpc5.11 promotor, which leads to expression in skeletal and cardiac muscle target tissues.”
In terms of safety, Geneton reported “good tolerability of GNT0004 in combination with transient immunological prophylactic treatment.”1 The organization noted that the trial, which began in 2021, had previously been paused after a serious adverse event (SAE) occurred in the first patient treated, but that the trial resumed in late 2022 after the SAE resolved.
The trial recruited patients aged 6 to 10 years old who are ambulant. The group of 5 who were treated includes 1 patient that was treated in the United Kingdom, with the other 4 having been treated in France. Genethon stated that it is currently making preparations for the pivotal European phase of the study in concert with the European Medicines Agency after having received a positive opinion from the Data Monitoring Committee.
In addition to DMD, Genethon is developing gene therapy products of a range of other diseases.3 Notably, clinical results for GNT-003 (GNT0003), an investigational AAV vector-based gene therapy being evaluated for the treatment of Crigler-Najjar syndrome in a phase 1/2 clinical trial (NCT03466463), were reported in The New England Journal of Medicine in August 2023.4 The patients with the rare liver disease who received the trial’s higher dose (n = 3; 5×1012 vg/kg) had a decrease in bilirubin levels and were not receiving phototherapy at least 78 weeks after vector administration.
“Although our study is small, among the patients who received the dose of 5×1012 vg/kg, GNT0003 restored UGT1A1 activity to levels that permitted suspension of phototherapy, and the efficacy persisted at 18 months after the treatment,” study author Lorenzo D’Antiga, MD, of the Department of Pediatric Hepatology, Gastroenterology, and Transplantation at Hospital Papa Giovanni XXIII, in Bergamo, Italy, and colleagues wrote.5 “A test of replication in a larger, well-characterized cohort of patients will be important.”
