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GenSight Biologics Inc. reports sustained visual acuity 78 weeks after gene therapy treatment for Leber’s Hereditary Optic Neuropathy (LHON)

GenSight Biologics Inc., (EURONEXT: SIGHT), Paris, France, have announced that their GS010 treatment for LHON provides sustained visual acuity 78 weeks after a dose escalating study in each cohort of 3 patients. The GS010 treatment 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. 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.


According to the company, patient data at 78 weeks shows that a mean change of visual acuity from baseline in the treated eyes was -0.61 LogMAR (p<0.001), or a mean improvement of +30 ETDRS letters. Control untreated eyes in contrast were reported to have a mean change from baseline of -0.31 LogMAR (p=0.0866), or +15 ETDRS letters. The company states that such data indicates a treatment effect of +15 letters (p=0.11) in favor of treated worse-seeing eyes however, no peer-reviewed primary data has been made available to date. In addition, the company report that patients treated within two years of onset of vision loss appear to fare even better, with a 20 ETDRS letter difference between treated and control eyes. The data announced by the company arises from approximately 20 patients with recruitment set to continue into Q12017.


Commenting on the achievement, Dr. Catherine Vignal, an investigator on the study and Chief of the Department of Ophthalmology at Rothschild Foundation Hospital, Paris, stated: “The confirmatory trends of week 48 data after 1.5 years of follow-up confirm significant hope for patients suffering from LHON. The insights gained from this and forthcoming data will be tremendously helpful as GenSight works to develop a therapy for this very severe disease with no existing curative treatment.”