GenSight Biologics has reported a natural history for LHON (with ND4 mutations) showing that a novel treatment could provide a convincing benefit. 

GenSight Biologics Inc., (EURONEXT: SIGHT), Paris, France, has announced the results from the final analysis of the REALITY natural history study, which reaffirms the poor prognosis for the vast majority of Leber Hereditary Optic Neuropathy (LHON) patients with vision loss due to a mutated ND4 mitochondrial gene.  REALITY is a multi-country retrospective and cross-sectional observational study of affected LHON subjects, based on subjects’ medical charts and the administration of surveys on Health-Related Quality of Life (HRQoL) and direct and indirect costs associated with the disease.  According to the company, the study will recruit at least 50 subjects (both adult and pediatric) chiefly in the following countries: Spain, Italy, France, United Kingdom, and the United States.  The primary objectives for the REALITY study are: to describe the evolution of visual functional and structural changes and other associated symptoms in patients with LHON; to understand the impact of LHON-related vision loss on the HRQoL; and to assess the economic burden for patients and their families arising from direct and indirect costs associated with the disease. The secondary objective is to describe the relationship between genetic, lifestyle and/or environmental factors and the expression of the LHON phenotype.


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.


The company had recently reported two trials in progress – the “RESCUE” and “REVERSE” studies – two separate randomized, double-masked, sham-controlled Phase III trials designed to evaluate the efficacy of a single intravitreal injection of GS010 (rAAV2/2-ND4) in subjects affected by LHON due to the G11778A mutation in the mitochondrial ND4 gene.  The trials were conducted in parallel, in 37 subjects for REVERSE and 39 subjects for RESCUE, in 7 centers across the United and EU.  The natural history report has now outlined that, “the REALITY findings bolster the case that the improvements we saw in REVERSE, RESCUE and the first analysis of CLIN06 (REVERSE and RESCUE) could not have arisen simply from spontaneous recovery among LHON patients.” Bernard Gilly, Co-founder and Chief Executive Officer of GenSight said, “we intend to bring this and other scientific evidence to the authorities to make a robust and convincing argument about the outstanding therapeutic benefit.”