GenSight Biologics Inc., Paris, France, are set to progress with gene therapy clinical trials following clearance from the U.S. Food and Drug Administration (FDA) for the company’s Investigational New Drug (IND) Application. The experimental therapy, “GS010” presents a potential treatment for Leber’s Hereditary Optic Neuropathy (LHON). The treatment (GS010) comprises a wild-type functional copy of the mitochondrial ND4 gene housed within an AAV2 vector and delivered via a single intravitreal injection. Delivery of the gene permits expression of the ND4 protein within the mitochondrial membrane aimed at bringing about rescue of the primary defect.
LHON has an estimated prevalence of 1 in 40,000 in Europe, and GenSight expects that 1,100 to 1,200 LHON patients will be seeking therapies for this disorder each year. The connection between LHON and mitochondrial DNA (mtDNA) arose following studies that reported a homoplasmic nucleotide transition from guanosine to adenosine at position 11778, resulting in an arginine-to-histidine substitution in ubiquinone oxidoreductase (NADH) subunit 4 (ND4) of the mitochondrial complex I. It is now known that the majority of LHON cases are associated with mutations in one of three mitochondrial genes that encode subunits of the same complex I of the mitochondrial respiratory chain. This complex I enzyme, containing 7 subunits encoded by mtDNA, is closely associated with the inner mitochondrial membrane, while a further 35 subunits, encoded by nuclear DNA, are imported into the organelle to facilitate specific steps of the respiratory pathway. Mitochondrial ND4 can only be translated inside the mitochondria (rather than on cytoplasmic ribosomes) as the TGA codon at amino acid 16 of the gene is read as tryptophan in the mitochondria but as a stop codon by the nuclear genetic code. An estimated 50% of LHON patients harbour the G11778A mutation and, as such, represent a significant patient population addressable with an ND4 gene therapy approach. The challenge in devising therapeutic strategies to tackle such mitochondrial disorders is to develop reliable delivery systems to transfer DNA into mitochondria by specially adapted techniques.
GenSight’s Phase III clinical studies are designed to achieve efficacy in subjects with LHON due to the G11778A mutation, and with up to one year onset of vision loss. According to the company, two trials will be conducted in parallel and will include patients with an onset of vision loss up to 6 months, and between 6 and 12 months respectively. The trials will seek to recruit up to 70+ patients at 7 sites in France, Germany, Italy, the UK and the United States. Commenting on the FDA clearance to progress with the studies, Pr. Nancy J. Newman, MD, Director of the Section of Neuro-Ophthalmology, Emory University School of Medicine, Atlanta, stated: “Patients are desperately waiting for a safe treatment for LHON. GS010 carries promise and could pave the way towards a novel therapy. We are eager to start enrolling patients in the US.”