LHON gene therapy affords sustained improvement in visual acuity paving the way to approval

The biopharma company GenSight Biologics, specialized in developing gene therapies for retinal degenerative diseases, recently published results of two Phase III clinical trials on the effect of LUMEVOQ gene therapy for Leber Hereditary Optic Neuropathy (LHON) patients. In September 2020, GenSight requested approval of LUMEVOQ to the European Medicines Agency (EMA) to treat LHON patients carrying a mutation in the ND4 mitochondrial gene.

LHON is a rare blinding bilateral optical neuropathy maternally inherited, affecting about 1 in 30,000 to 1 in 50,000 people, particularly young adults males. It is characterized by the selective degeneration of retinal ganglion cells and their axons, resulting in a rapidly progressive and irreversible vision loss. It is the most common mitochondrial DNA (mtDNA) disorder, caused by mutations in one of four mitochondrial genes (MT-ND1MT-ND4MT-ND4L, or MT-ND6). Three mtDNA point mutations account for around 90% of all LHON cases, being a mutation in the MT-ND4 gene (m.11778G>A) the most frequent. This gene encodes the NADH dehydrogenase 4, one protein of a large enzyme complex in mitochondria (complex I) necessary to produce energy for the cells.

The gene therapy LUMEVOQ (GS010, lenadogene nolparvovec) was designed with a methodology developed at the Institute de la Vision in Paris to repair mitochondrial genetic defects. The gene of interest –in this case ND4– is introduced into retinal ganglion cells using an AAV (adeno-associated virus) vector able to produce the functional protein ND4.

GenSight has conducted several clinical trials with this therapy. Among them, the REVERSE and RESCUE phase III studies. In the REVERSE assay participated 37 patients with an onset of vision loss from 6 months to one year before enrollment, whereas in the RESCUE trial were included 39 patients who experienced vision loss within 6 months in at least one eye, and in both eyes no longer than 6 months before enrolment. The therapeutic gene transfer was performed by intravitreal injection in one eye, and the other eye was treated with a placebo.

Data from the REVERSE clinical trial were published in Science Translational Medicine. Patients showed sustained improvement in visual function in both eyes from unilateral injection of the therapeutical gene. It was shown in non-human primates that the unexpected improvement in the contralateral eye was due to the transfer of the vector from one eye to the other. Results from the RESCUE trial , showed bilateral improvement of visual acuity comparable to the REVERSE clinical assay and also that the therapy was well-tolerated. The results of this study have been published in Ophthalmology.

Results from a third phase III trial (REFLECT) will be presented during the second quarter of 2021 and the EMA is expected to make the approval before 2022.

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