Promising Results for Gene Therapy in LHON

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This month, News in Review highlights selected papers from the original papers sessions at AAO 2020 Virtual. Each was chosen by the session chairs because it presents important news or illustrates a trend in the field. For details of presentation times, check the Virtual Meeting Guide at either aao.org/2020 or in the virtual meeting platform.

Two years after a single gene therapy injection, patients with Leber hereditary optic neuropathy (LHON) have experienced significant visual improvement.¹

YOUNG PATIENT WITH LHON. Fundus photographs in this 17-year-old patient show hyperemic optic discs with blurred margins and moderately tortuous vasculature. The left optic disc shows mild temporal pallor.

Two clinical trials. In the two ran­domized sham-controlled phase 3 trials known as RESCUE and REVERSE, 76 patients with LHON received a single unilateral, intravitreal injection of an adeno-associated viral vector, rAAV2/ 2‑ND4 (Lumevoq, GenSight Biologics). They also received a simulated sham in­jection in their fellow eyes, said Patrick Yu-Wai-Man, MD, PhD, at the Uni­versity of Cambridge, Moorfields Eye Hospital, and the University College London Institute of Ophthalmology.

The RESCUE trial evaluated patients who had onset of vision loss up to six months before treatment; the REVERSE trial evaluated those who ex­perienced vision loss six to 12 months before treatment. The viral vector car­ries a replacement for the mitochondri­al ND4 gene. When defective, this gene leads to rapid loss of retinal ganglion cells because of mitochondrial dysfunc­tion; this is followed by degeneration of the optic nerves with visual failure.

VA outcomes. Visual acuity (VA) in the treated eyes improved by 26 EDTRS letters from the worst measured vision in the early-treatment group and by 28 letters in the late-treatment group, Dr. Yu-Wai-Man said. “The improvement that we observed is more than what would be expected based on the natural history of untreated patients,” he said.²

However, both the RESCUE and REVERSE trials produced an unexpect­ed finding: The untreated contralateral eyes had VA gains comparable to those of the treated eyes.³ Two other LHON gene therapy research groups, in Miami and in Wuhan, China, have also report­ed this bilateral effect in their studies. Dr. Yu-Wai-Man will discuss possible reasons for this bilateral improvement in his AAO 2020 Virtual presentation.

European marketing. In September, GenSight Biologics submitted a mar­keting application for Lumevoq to the European Medicines Agency. To date, nearly 200 patients have been treated with the viral vector through trials and compassionate-use exceptions.

—Linda Roach

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1 Yu-Wai-Man P et al. Efficacy of gene therapy for Leber hereditary optic neuropathy: Final re­sults of the phase 3 RESCUE and REVERSE trials. Presented at: AAO 2020 Virtual; Nov. 13-15, 2020.

2 Newman NJ et al. J Neuroophthalmol. In press.

3 Yu-Wai-Man P et al. Sci Transl Med. In press.

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Relevant financial disclosures—Dr. Yu-Wai-Man: GenSight Biologics: C.

For full disclosures and the disclosure key, see below.

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