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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”.