First Step in Gene Therapy for Rare Form of Blindness

Ricki Lewis, PhD

January 15, 2014

Choroideremia joins the list of single-gene diseases that respond to gene therapy, according to results of a phase 1/2 clinical trial published online January 15 in the Lancet. The findings are a first step toward the goal of salvaging islands of functioning photoreceptors sufficiently to halt retinal degeneration.

Choroideremia is caused by mutation of the CHM gene, which encodes Rab escort protein 1 (REP1). Because the gene is X-linked, all patients are male. A female could inherit the condition if her mother were a carrier and her father were affected, but because the disease is so rare (1 in 50,000), this is unlikely.

The disease was first described in 1872, and the gene was cloned in 1990, one of the discoveries that coincided with the launch of the human genome project. Choroideremia affects the retina, retinal pigment epithelium (RPE), and choroid, exposing the underlying sclera in patches.

"Usually a teenage boy will start losing night vision. Later he loses the peripheral visual field, and then, perhaps in his 40s or 50s, loses central vision until he is legally blind," Matthew During, MD, PhD, a professor of neuroscience at the College of Medicine, Ohio State University Medical Center, Columbus, and the coauthor who designed the viral vector, told Medscape Medical News.

Excellent Gene Therapy Candidate

Gene therapy makes sense for choroideremia. The gene is small (1.9-kb coding sequence), the target tissue is accessible, and the central retina is thick enough to withstand the retinal detachment necessary to deliver the vector. "The cellular degeneration is slow, providing a large window of time in which to intervene before the onset of visual loss," lead author Robert E MacLaren, MD, PhD, professor of ophthalmology at the Nuffield Laboratory of Ophthalmology, Department of Clinical Neurosciences, University of Oxford, told Medscape Medical News.

Gene therapy for an inherited visual disorder has a powerful precedent: Leber congenital amaurosis type 2, caused by mutation in the RPE65 gene. More than 200 individuals have had the gene therapy in several clinical trials since 2007, and dozens are enjoying impressive visual improvement, some for more than 3 years.

Choroideremia presents different challenges. "RPE65 LCA is a dysfunctional retina plus degeneration, so bringing in healthy genes can rescue the function. But in choroideremia, the dysfunction is exclusively due to degeneration," Hendrik Scholl, MD, professor of ophthalmology at the Wilmer Eye Institute of Johns Hopkins University School of Medicine in Baltimore, Maryland, told Medscape Medical News. Dr. Scholl wrote an accompanying comment with José A. Sahel from the Institut de la Vision, Paris, France, among other affiliations.

First Trial Shows Promise

In the open-label dose-escalation trial, the researchers introduced 6 to 10 billion adeno-associated virus 2 vectors bearing wild-type CHM beneath the fovea of 1 eye of 6 male patients aged 35 to 63 years. The untreated eyes served as controls. Prior to treatment, 2 patients had normal foveas, 2 had partial foveal collapse, and 2 had complete foveal loss.

Tests conducted at baseline and 6 months postsurgery included visual acuity, microperimetry to assess visual function in the treated area, and retinal sensitivity. Autofluorescence imaging to detect products of the visual cycle in the RPE revealed regions of surviving tissue.

By the 6-month mark, all 6 patients had recovered visual acuity from before the retinal detachment, and the 2 most severely affected patients improved, with one reading 3 additional lines on an eye chart. In the patient with no fovea, fixation shifted to a treated island, rather than to an untreated island, an apparent adaptation also seen in RPE65 trials.

The treated eyes showed increased light sensitivity (mean, 1.7 [SE, 1.0]) that correlated to vector dose per square millimeter of surviving retina (r, 0.82; P = .04). Control eyes demonstrated nonsignificant reductions (P > .05) for maximal sensitivity (−0.8 dB [SE, 1.5]) and mean sensitivity (−1.6 dB [SE, 0.9]). Maximal sensitivity measured with dark-adapted microperimetry increased in the treated eyes from 23.0 dB (SE, 1.1) at baseline to 25.3 dB (SE, 1.3) after treatment (increase, 2.3 dB; 95% confidence interval, 0.8 - 3.8).

The time frame of the current report is too short to assess effects on slowing or halting retinal degeneration, but it is only the start. "Another 6 patients are being treated with higher doses, and we are following the ongoing 6 patients to make sure that the gains are real," Dr. During told Medscape Medical News.

Further investigation will address optimal delivery time, which should be before significant retinal thinning. In children, retinal sensitivity near the fovea is detectable when visual acuity is still good, and could therefore act as an early marker.

Gene therapy might even be administered before symptoms arise if genetic testing identifies affected family members. "At this early stage of the trial, we used advanced cases, but ultimately we will move earlier. Treating presymptomatically would be great," Dr. During said.

Dr. Scholl foresees gene therapy of even modest effect for choroideremia teamed with other approaches to preserve vision, such as supplying channel rhodopsin, halorhodopsin, or ciliary neurotrophic growth factor. However, gene therapy alone may work. "Our hope is that gene therapy for choroideremia will become the standard of care," Dr. During concluded.

"It's an exciting time for monogenic retinal degeneration diseases that have been known for being untreatable for decades," Dr. Scholl added.

Dr. MacLaren, Dr. During, and Dr. Seabra are coinventors on a UK patent application for the vector. Dr. During is a director of Gene Technology Solutions, Auckland. The other authors have disclosed no relevant financial relationships. Dr. Scholl is a consultant for Fovea Pharmaceuticals, Trevena, Guidepoint Global, and Gerson Lehrman Group; a member of Data Monitoring Committees for StemCells and Genzyme; and receives research funding through his institution from QLT Therapeutics. Dr. Sahel is a consultant for Sanofi-Fovea and Genesignal; a founder and consultant to Pixium Vision and GenSight Biologics; and receives research funding through his institution from Oxford Biomedica, Novartis, Allergan, Bayer, Second Sight, and Alcon. Dr. Lewis is the author of The Forever Fix: Gene Therapy and the Boy Who Saved It (St. Martin's Press, 2012) about the RPE65 gene therapy trial. She owns stock in QLT.

Lancet. Published online January 15, 2014.

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