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French biopharmaceutical company, GenSight Biologics, reports long-term data for gene therapy treatment of LHON

GenSight Biologics (Euronext: SIGHT) have reported 30 months of follow-up data from a Phase I/II clinical trial with their treatment (GS010) in patients with Leber hereditary optic neuropathy (LHON). The results of the study indicate that long-term sustained gains in visual acuity appear to persist for 30 months following a single intravitreal injection in subjects with less than 2 years of onset of vision loss. 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.


According to data released by GenSight, participants in the Phase I/II study had an average onset of vision loss of 6 years at the time of treatment, with an off-chart median visual acuity. At month 30, participants treated with the therapy, and with relatively better vision at the time of treatment (<2.79 LogMAR), showed a mean gain of +28 ETDRS letters (-0.55 LogMAR) compared to baseline. In contrast, untreated participants had a mean gain of +13 ETDRS letters (-0.25 LogMAR), as compared to baseline. The difference of +15 ETDRS letters in favor of treated patients was deemed clinically significant. Commenting on the milestone, Dr. Catherine Vignal, an investigator of the study and Chief of the Department of Ophthalmology at the Rothschild Foundation Hospital, Paris, stated, “the confirmatory safety and continued positive trends after 2.5 years of follow-up constitute significant hope for patients suffering from LHON. It is worth noting that the observed improvement in some of the untreated eyes was consistent with several prior studies in neuroretinal degenerative diseases. The insights gained from this and forthcoming data will be tremendously helpful, as GenSight works to develop a therapy for this severe blinding disease affecting patients in the prime of their life, and for which no curative treatment exists.” The experimental GS010 treatment is currently progressing through the final stages of two Phase III clinical studies (RESCUE and REVERSE), in the EU and the United States, and expected to provide results in the second and third quarters of 2018, respectively.