Bilateral visual improvement with unilateral gene therapy injection for Leber hereditary optic neuropathy

Abstract

REVERSE is a randomized, double-masked, sham-controlled, multicenter, phase 3 clinical trial that evaluated the efficacy of a single intravitreal injection of rAAV2/2-ND4 in subjects with visual loss from Leber hereditary optic neuropathy (LHON). A total of 37 subjects carrying the m.11778G>A (MT-ND4) mutation and with duration of vision loss between 6 to 12 months were treated. Each subject’s right eye was randomly assigned in a 1:1 ratio to treatment with rAAV2/2-ND4 (GS010) or sham injection. The left eye received the treatment not allocated to the right eye. Unexpectedly, sustained visual improvement was observed in both eyes over the 96-week follow-up period. At week 96, rAAV2/2-ND4–treated eyes showed a mean improvement in best-corrected visual acuity (BCVA) of −0.308 LogMAR (+15 ETDRS letters). A mean improvement of −0.259 LogMAR (+13 ETDRS letters) was observed in the sham-treated eyes. Consequently, the primary end point, defined as the difference in the change in BCVA from baseline to week 48 between the two treatment groups, was not met (P = 0.894). At week 96, 25 subjects (68%) had a clinically relevant recovery in BCVA from baseline in at least one eye, and 29 subjects (78%) had an improvement in vision in both eyes. A nonhuman primate study was conducted to investigate this bilateral improvement. Evidence of transfer of viral vector DNA from the injected eye to the anterior segment, retina, and optic nerve of the contralateral noninjected eye supports a plausible mechanistic explanation for the unexpected bilateral improvement in visual function after unilateral injection.

Intravitreal Gene Therapy vs. Natural History in Patients With Leber Hereditary Optic Neuropathy Carrying the m.11778G>A ND4 Mutation: Systematic Review and Indirect Comparison

“…In both studies, lenadogene nolparvovec was injected in one eye, while the fellow eye received a sham injection, with the unexpected result of sustained visual improvement in both eyes. At 96 weeks post-injection, the mean gain from nadir (worst vision point) in REVERSE and RESCUE studies was, respectively, +28 and +26 in treated eyes and +24 and +23 ETDRS letters in sham eyes (14,15). The REVERSE and RESCUE patients are currently followed in an extension study for up to 5 years after injection (CLIN06, NCT03406104).…”

Gene Therapy for Inherited Retinal Disorders: Update on Clinical Trials

“…Thereafter, the eyes started to improve by + 10 from the plateau until the end of the study at week 96. Unexpectedly, in both studies, the untreated eye also improved by + 13 and + 9 ETDRS letters, respectively, which was attributed to the transfer of vector DNA to the fellow eye [31,32]. EU marketing authorization was submitted with a decision by the European Medicines Agency to be expected in the second half of 2021.…”

“…All three programs use the AAV2 capsid in combination with intravitreal delivery to target RGCs (▶ Table 1). The most advanced drug candidate lenadogene nolparvovec [31,32] recently completed phase III. When treated at a mean disease duration of 8.8 months, treated eyes showed a mean improvement of 15 ETDRS letters at week 96 and 68 % had a clinically relevant recovery in BCVA from baseline in at least one eye.…”

Gene Therapy: A Possible Alternative to CFTR Modulators?

“…In 2012, the first viral gene-therapy treatment was approved in Europe for treatment of lipoprotein lipase deficiency (Yla-Herttuala, 2012) and showed good results even years later (Gaudet et al, 2016). Recently, gene therapy also showed promising results for Leber hereditary optic neuropathy by improving bilateral vision in patients over 96 weeks of followup after a unilateral intravitreal injection (Yu-Wai-Man et al, 2020). These successful trials were carried out on easily accessible hematopoietic stem cells or by direct vectors injections into specific tissues, which may explain previous trials failure in CF compared to other diseases.…”