Long term vision results following retinal gene therapy for choroideremia

Abstract

Purpose : The long term stability of visual function improvements following retinal gene therapy for Leber congenital amaurosis using adeno-associated viral (AAV) vectors has recently been questioned. We therefore sought to determine the long term effects of AAV retinal gene therapy for choroideremia in the first six patients undergoing treatment for this condition.

Methods : Patients were recruited into an open label dose escalation study (NCT01461213). An AAV2 vector encoding the choroideremia gene and a Woodchuck hepatitis virus post-transcriptional regulatory element (AAV.CHM.WPRE) was injected subretinally at a dose of 10¹⁰ genome particles (gp) in five patients (P1-5) and 0.6x10⁹ in P6. Visual acuity (VA) was measured using the Early Treatment for Diabetic Retinopathy study (ETDRS) charts. Microperimetery was measured in mean decibels (dB).

Results : For the five patients receiving 10¹⁰ gp of AAV.CHM.WPRE, the mean ETDRS VA change at 2 years was +4.4±4.2 letters in the treated eyes and -2.4±1.9 letters in the unoperated control eyes. At the last follow up timepoint at 3.5 years (after cataract surgery in 3 of 5 patients), the mean (±SEM) VA change was +8.4±4.7 letters in the treated eyes and -8.8±3.1 letters in the control eyes, equivalent to a mean difference of over three ETDRS lines. The treated eyes had become dominant in all five of these patients. P6 who received a lower dose of 6x10⁹ gp showed a steady decline in VA in both eyes, losing 29 and 18 letters in his treated and untreated control eyes, respectively. By 4 years, P1 who has not yet undergone cataract surgery, had a sustained gain of 22 letters in his treated eye with loss of 26 letters in his control eye - a relative change of approximately 10 ETDRS lines between the two eyes over this time. Microperimetry was broadly similar, with mean changes of -0.7±0.4 dB and -2.0±0.6 dB in the treated and untreated eyes of P1-5 respectively at 2 years. An improvement in the pattern electroretinogram (PERG) was seen only in the treated eye of P3, the patient with the best baseline visual function.

Conclusions : Early VA improvements noted in two patients following gene therapy were sustained for up to 4 years. Three further patients who had near maximal VA in their treated eyes at baseline maintained it, despite losing VA in their unoperated eyes over this time. One patient did not show any apparent response to gene therapy at the 6 x 10⁹ gp dose.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.