Retinal Gene Therapy for Choroideremia in a Multicenter Dose Escalation Phase I/II Clinical Trial

Abstract

Purpose : Choroideremia is a currently incurable X-linked retinal degeneration. Here we report the final results of a non-randomised phase I/II clinical trial assessing retinal gene therapy using an adeno-associated virus serotype 2 (AAV2) vector expressing the choroideremia transgene (REP1) at the 2-year primary endpoint.

Methods : In total 14 patients were recruited, 12 of whom received subretinal gene therapy as per protocol without complications. Doses ranged from 6x10⁹ to 1x10¹¹ genome particles of AAV2.REP1. The primary outcome measure of safety and efficacy was visual acuity at 2 years.

Results : Over the entire group of 14 patients, by 2 years the median visual acuity improved by 4.5 letters in the treated eyes compared with a loss of 1.5 letters in the untreated eyes (p=0.04). For the 12 patients receiving gene therapy without complications, the treated eyes had gained 5.5 letters above their baseline level by 2 years (p=0.02). Compared to the untreated eyes, by 2 years this represented a median 4.5 letter gain in favour of the eyes receiving gene therapy (p=0.001). By this time, 6 of the 12 treated eyes had gained more than one line of vision (>5 letters), compared with none of the 12 untreated eyes. The adverse events in the two patients who were treated off protocol related to surgically induced retinal thinning with under-dosing in one case and inflammation (vitritis and choroiditis) in the other. The complications in these two patients led to visual acuity losses of 15 and 14 letters, respectively by 2 years. Changes to the protocol were made midway through the trial to reduce the chance of these complications occurring in future. These included introduction of an automated subretinal injection system, intra-operative OCT and an extended course of post-operative immune suppression. At the last follow up (range 2-5 years), visual acuity had been maintained or increased in all 12 study eyes that had received gene therapy as per protocol, compared with only 4 of the 12 untreated eyes. This was equivalent to a mean difference of 16.0 letters (>3 lines) between eyes.

Conclusions : In general, retinal gene therapy for choroideremia appears to be safe. It sustained and improved visual acuity in a cohort of predominantly late stage patients in whom rapid visual acuity loss would ordinarily be predicted. Longer term follow-up in a fully randomised clinical trial is needed to confirm these observations.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.