Retinal gene therapy has an unexpected benefit for choroideremia patients

By Lorraine L. Janeczko

NEW YORK (Reuters Health) - Retinal gene therapy for choroideremia was safe - and produced improvements in vision - in a phase 1/2 clinical trial from the United Kingdom.

Choroideremia, a currently incurable X-linked recessive blinding disease that progresses slowly over decades, is caused by mutations in the CHM gene, which encodes the Rab escort protein 1 (REP1). It is rare, with a prevalence of about 1:50,000, the study authors wrote online January 16 in The Lancet.

"This is the first time choroideremia has been treated with gene therapy. Since it was identified almost 150 years ago, this and other degenerative retinal diseases have largely been considered untreatable, but we show in this study that gene therapy might partially restore lost function," said study co-author Dr. Matthew J. During of The Ohio State University in Columbus, in an email to Reuters Health.

"Indeed, in the two subjects in the trial whose disease was most advanced, we obtained clinically important improvements in visual acuity," he added.

"Moreover, this approach was safe, and the results of retinal imaging and functional studies suggest that the approach might prevent or delay ongoing degeneration. We will need, though, to follow these patients for a couple of years to be confident about the effect on the natural history of the disease," he said.

In their multicenter clinical trial, Dr. During and his colleagues examined the effects of treating six male choroideremia patients with retinal gene therapy using an adeno-associated viral (AAV) vector encoding REP1 (AAV.REP1). The patients were between 35 and 63 years of age and their disease stages at baseline ranged from normal foveal structure through partial foveal collapse to complete foveal loss.

The researchers tested the patients for best corrected visual acuity, microperimetry, and retinal sensitivity at baseline and six months after surgery, used the untreated eyes as controls, and compared the differences.

During surgery, the researchers detached the retina through a Teflon cannula using a balanced salt solution. Once the retina was detached from the retinal pigment epithelium (RPE), they injected genome particles of AAV2.REP1 through a fresh syringe into the subretinal space that they had created.

Their findings surpassed their expectations. Retinal detachment normally reduces vision, but six months after surgery, two advanced choroideremia patients with low baseline best corrected visual acuity gained 21 letters and 11 letters, equivalent to more than two and four lines of vision. Four other patients with near normal baseline best corrected visual acuity had a marginal loss of one to three letters.

The mean overall gain in visual acuity was 3.8 letters, a Snellen equivalent (SE) of 4.1. The maximal sensitivity in the treated eyes, measured with dark-adapted microperimetry, increased from 23.0 dB (SE 1.1) at baseline to 25.3 dB (SE 1.3) after treatment (95% CI 0.8 to 3.8).

In all patients, the increase in retinal sensitivity in the treated eyes (mean 1.7; SE 1.0) correlated with the vector dose given per square millimeter of surviving retina (r=0.82; p=0.04).

The researchers also found small non-significant reductions in the control eyes in both maximal sensitivity (-0.8 dB; SE1.5) and mean sensitivity (-1.6 dB; SE 0.9). The one patient whose fovea was not treated with the vector re-established his variable eccentric fixation to include the treated ectopic island of surviving RPE.

"I was surprised by two findings," said Dr. Hendrik P. N. Scholl of the Wilmer Eye Institute of The Johns Hopkins University in Baltimore, Maryland, in a phone interview. "First, artificial detachment of the retina, which was part of the procedure, had no harmful consequences. Second, this was basically a safety trial, and the investigators hoped to observe that patients would remain at baseline after the observation period. That some patients gained significant vision was certainly a surprise."

Dr. Scholl, who was not involved in the study, coauthored an editorial with Dr. José-Alain Sahel, founder of the Institut de la Vision in Paris, France.

Dr. Robert MacLaren of the University of Oxford, UK, who led this trial, said in a press release, "This has huge implications for anyone with a genetic retinal disease such as age-related macular degeneration or retinitis pigmentosa, because it has for the first time shown that gene therapy can be applied safely before the onset of vision loss."

"These results complement those of the earlier ocular gene therapy studies, particularly on Leber's congenital amaurosis, and they are a significant advance," Dr. During told Reuters Health.

"Our data also suggest that before the cells in the retina die, they can potentially be rescued with our approach and have function restored, leading to improvements in retinal sensitivity and visual acuity," he added.

"It will be very important to see whether the gains we observed in this study persist, and whether the natural history of the disease is altered. Those results will likely take another year. The retina in particular appears to be an excellent target for gene therapy, and a number of groups worldwide are now tackling other retinal degenerative diseases. Hence, as a clinician you can expect to see significant advances in retinal gene therapy, which finally appears to be coming of age," he added.

Looking toward future research, the researchers are now planning a phase III study that will most likely begin in 2015 or 2016 and have results a year or so later.

Co-author Dr. Frans P. M. Cremers of Radboud University Medical Center in Nijmegen, the Netherlands, who discovered the choroideremia gene in 1990, observed in an email, "This study of choroideremia, a rare disorder only affecting only males, is important as it is only the second published gene therapy trial for inherited retinal diseases in humans. The eye field no doubt is leading the way for different types of treatment."

In related news, Reuters reported January 30 that Oxford University scientists have formed NightstaRx, a biotechnology company to create gene therapies to treat choroideremia and other blinding diseases.


Lancet 2014.

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