Month: 01 Jan 2019
Issue: not yet available
Beneficial effects of retinal gene therapy show continuing treatment over 2-year endpoints
Researchers from the Nuffield Laboratory of Ophthalmology, University of Oxford, UK, demonstrate that clinical data on a choroideremia gene therapy study among 14 UK patients showed that visual acuity improved in the 14 treated eyes over controls (median 4.5 letter gain, versus 1.5 letter loss, P = 0.04), with 6 treated eyes gaining more than one line of vision (> 5 letters). In a letter published in Nature Medicine, the study’s principal investigator, Prof. Robert MacLaren, reported that the primary endpoint was vision change in treated eyes 2 years after surgery compared to unoperated fellow eyes.
Choroideremia is an X-linked recessive disease with an estimated prevalence of 1 in 50,000 and is currently incurable. Successful proof-of-concept holds significant implication not only for treatment of choroideremia but also for treatment of a number of other retinal degenerations including retinitis pigmentosa (RP) and age-related macular degeneration (AMD). The Phase I/II trial conducted by Prof. MacLaren and colleagues from Department of Clinical Neurosciences, University of Oxford, and Imperial College London, UK, uses an adeno-associated virus (AAV serotype 2 vector) as the delivery vehicle to transport a copy of a functioning choroideremia gene (CHM) encoding the Rab escort protein-1 (REP1). The therapeutic transcript is flanked upstream by a chicken-derived beta actin promoter with a cytomegalovirus enhancer flanking a rabbit beta-globulin intron/exon splice site (collectively termed CAG promoter) to ensure constitutive expression and a downstream woodchuck viral hepatitis regulatory element to enhance gene expression. The prospective therapy was delivered surgically by sub-foveal injection and comprised of either a full low dose of 1 X 10^10 or high dose of 1 X 10^11 genome particles (gp). Assessment of therapeutic benefit involves a variety of functional tests including best corrected visual acuity (BCVA), micro-perimetry and retinal sensitivity assays to compare pre- and post-surgical values.
In concluding their paper on data out to month 24, the authors of the study commented that, “the results of this phase 1/2 clinical trial show that gene therapy for choroideremia is generally safe. Small but sustained visual acuity gains were seen over a period of several years in end-stage eyes, in which rapid visual acuity loss would ordinarily be expected, with several patients experiencing gains of three lines or more, an improvement widely accepted to be clinically significant”.Back to previous