Gene Therapy for LHON

Mitochondrial gene replacement therapy restores vision in Leber’s hereditary optic neuropathy patients. Roibeárd O’hÉineacháin reports. Gene therapy with the AAV2 viral vector LUMEVOQ® (GS010, GenSight Biologics) shows encouraging results in patients with Leber’s hereditary optic neuropathy (LHON), according to Patrick Yu-Wai-Man MD, PhD. He noted that in two phase III studies—the RESCUE and REVERSE trials—vision improved in 78% of LHON patients who underwent the gene therapy to replace the defective mitochondrial gene. Patients tolerated the treatment well and, overall, vision improved by about five lines on the visual chart at two years after receiving the injection. In addition, the patients’ vision has so far continued to improve at up to 52 months of follow-up. “Gene therapy is a very promising and attractive treatment strategy for LHON. Research is still ongoing, but vision can improve if you correct the underlying genetic defect,” he said. FROM GENE DISCOVERY TO THERAPY Professor Yu-Wai-Man explained LHON is an inherited mitochondrial disease that causes dysfunction of the retinal ganglion cells and degeneration of the optic nerve. First described in 1871 by the German ophthalmologist Theodore Leber, this genetic disorder tends to affect young men in their 20s and 30s, and its defining clinical feature is rapid and severe loss of central vision in both eyes. Visual recovery is poor, and most patients fulfil the criteria for blind registration. In 1988, researchers identified a mutation at position 11778 of the mitochondrial genetic code, which affects the MT-ND4 gene, as the most common cause of LHON. The 11778 ND4 mutation accounts for 60–70% of LHON cases and two other genetic defects at positions 3460 and 14484 account for 10–15% of cases. Introducing genes into mitochondria is technically challenging because mitochondria have both an inner and outer membrane, which are relatively difficult to penetrate Prof Yu-Wai-Man said. He said using an inactivated adeno-associated viral vector (AAV2) to deliver the replacement gene (MT-ND4) into the nuclear genome helps get around this problem. The gene product has a special “mitochondrial targeting sequence” that acts like a homing device directing the protein to the right location in the cell and facilitating its import into the mitochondria. VISUAL IMPROVEMENT The RESCUE study included 39 LHON patients who had been affected for up to six months, whereas the REVERSE study included 34 patients who had been affected for six to 12 months. All patients were 15 years or older and were confirmed carriers of the 11778 MT-ND4 mutation. In both trials, patients received an intravitreal injection of the viral vector (rAAV2/2-ND4) in one eye and a sham injection in the fellow eye. In the RESCUE study, vision continued to worsen in the first 48 weeks following injection, by which time the eyes lost a mean of around 20 letters, equivalent to about four lines on the visual chart. However, vision began to improve afterwards, and by two years, an average improvement of 26 and 28 letters from the nadir was observed in the RESCUE and REVERSE studies, respectively. The visual recovery seen in these two trials was more than expected based on the natural course of the disease in patients with LHON carrying the 11778 MT-ND4 mutation. Unexpectedly, the non-injected (sham) eyes showed a parallel visual improvement in both studies. In a subsequent nonhuman primate study, researchers detected viral vector DNA in the fellow non-injected eye when an intravitreal injection of AAV2/2-ND4 was given to one eye only, providing a possible explanation for the bilateral visual improvement seen in treated patients. The researchers are planning long-term follow-up studies of the patients in the RESCUE and REVERSE trials. In the meantime, preliminary results from the REFLECT study indicate LHON patients carrying the 11778 mutation seemed to achieve a slightly better visual outcome when both eyes were treated with AAV2/2-ND4 rather than just one eye. Future studies will address the question of the ideal timing of the treatment and whether treatment is beneficial in patients with chronic LHON who have been affected for more than one year. This study was presented at the Fighting Blindness Retina 2021 Meeting in Dublin, Ireland. Professor Patrick Yu-Wai-Man MD, PhD, FRCPath, FRCOphth is an NIHR Advanced Fellow and an Honorary Consultant Neuro-ophthalmologist based at Moorfields Eye Hospital, London, UK; Addenbrooke’s Hospital, Cambridge, UK; and the University of Cambridge, UK. py237@cam.ac.uk