Early gene therapy could improve choroideremia prognosis

Apr 30 2014

By Sarah Pritchard, medwireNews Reporter

Retinal gene therapy could prevent loss of vision in patients with choroideremia and other retinal diseases, show the results of a phase I/II study.

The researchers report in The Lancet that there were no obvious detrimental effects from the detachment and treatment of the fovea with an adeno-associated viral (AAV) vector encoding the Rab escort protein 1 (REP1).

They explain that choroideremia leads to blindness due to mutations in the CHM gene, which encodes REP1. And while good visual acuity is generally maintained until the degeneration reaches the fovea, identifying underlying changes in retinal activity could indicate the functional effects of gene therapy.

Six male patients aged between 35 and 63 years with choroideremia and null mutations in the CHM gene received up to 1.0x10¹⁰ genome particles of AAV.REP1 in one eye by subfoveal injection after surgical retinal detachment, with five eyes receiving the full dose. The participants were also treated with a 10-day course of oral prednisolone.

The overall mean gain in visual acuity was 3.8 letters on the Early Treatment for Diabetic Retinopathy Study (ETDRS) system, report Robert MacLaren (University of Oxford, UK) and colleagues. However, gains were in fact only seen in two patients who had a reduced visual acuity at baseline: one gained 21 letters and one gained 11 letters.

The remaining four participants each had a baseline visual acuity better than 6/9 (using the Snellen test) and had a marginal loss of letters on the ETDRS system at 6 months after receiving the vector, report MacLaren et al.

Maximal retinal sensitivity also improved at 6 months in the five eyes administered the full dose of vector, increasing by 2.5 dB. By contrast, retinal sensitivity fell by 2.3 dB in the sixth eye, which had the largest target area, but received a reduced dose of vector due to difficulties with retina detachment.

The researchers note that concerns have been raised regarding the effect of foveal gene therapy on the thickness of the outer retina; however, they found the thickness of the retina to be similar before and 6 months after surgery and gene therapy, at 175 µm and 169 µm, respectively.

“The results show the potential for gene therapy, not just in the treatment of choroideremia, but also for other chronic retinal degenerations that require early intervention before the onset of visual loss”, remarks the research team. They suggest age-related macular degeneration could be one such disease that might benefit from the novel approach.

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