Improved visual function in patients with choroideremia undergoing subretinal gene therapy

Abstract

 

Purpose

 

To report the results of a gene therapy clinical trial using an adeno-associated viral (AAV) vector encoding Rab escort protein (REP)1 in six patients with a diagnosis of choroideremia.

 

Methods

 

An AAV vector (serotype 2) was constructed with a modified CBA promoter that incorporated a synthetic intron upstream of the gene encoding REP1, coupled downstream to a modified Woodchuck hepatitis virus post-transcriptional regulatory element (WPRE) and bovine polyA signal. After 23 gauge pars plana vitrectomy, the vector was delivered by subretinal injection in 6 patients with choroideremia at a dose of 10¹⁰ genome particles (gp) in five patients and 6 x 10⁹ in the sixth. The foveal region was detached in all patients, four of whom had per-operative vision of 20/30 or better. Visual function was assessed with visual acuity (VA) and microperimetry at baseline followed by 6 months and one year post-surgery. Anatomical changes were assessed with optical coherence tomography and autofluorescence.

 

Results

 

Six months after surgery, the visual acuity improved by two lines and four lines in the two patients in whom VA was less than 20/30 at baseline - this improvement was sustained at one year. VA returned to within one line of baseline in the other four patients. Despite undergoing foveal detachment, there was a mean improvement in retinal sensitivity in the treated eyes (+0.63 dB) compared to the control eyes (-0.60 dB) one year after gene therapy (95% confidence interval of difference: +0.05 to +2.40 dB). Within this group, improvements in retinal sensitivity were correlated to the total dose of vector administered per mm² of retina measured by autofluorescence. Mild progression of cataract was noted in treated eyes but in contrast to previous studies, no significant retinal thinning was observed.

 

Conclusions

 

Improvements in retinal sensitivity and visual acuity were observed at six months and sustained for up to one year in choroideremia patients undergoing retinal gene therapy. Since foveal detachment, post-vitrectomy cataract and progressive retinal degeneration would ordinarily be associated with a reduction in vision over this period, the sustained improvements seen show the potential of gene replacement therapy when applied before the onset of foveal thinning and validate the concept of subretinal gene delivery predicted by the preclinical studies over recent years.

 

 

Gene therapy for chroideremia

 

Keywords: 696 retinal degenerations: hereditary • 538 gene transfer/gene therapy • 648 photoreceptors