An experimental gene therapy continued to improve the vision of some patients with choroideremia at 3.5 years of follow-up in a phase 1/2 clinical trial.

In showing efficacy for this length of time, the treatment cleared the hurdle that stymied a similar therapy for a related condition, Leber's congenital amaurosis, and it raised hope of a cure for choroideremia, which almost always leads to blindness, American Academy of Ophthalmology spokesperson Raj Maturi, MD, told Medscape Medical News.

"At this point, there is no real treatment for it," said Dr Maturi, a retina specialist in Indianapolis, Indiana, who was not part of the study. "This is the most wonderful thing that can happen to a patient with choroideremia."

The study appears as a letter to the editor published online April 27 in the New England Journal of Medicine.

The disease occurs when a mutation of the CHM gene on the X chromosome interferes with production of the RAb escort protein-1 (REP-1). This disrupts the ability of the protein to aid in intracellular trafficking.

In other tissues, REP-2 can make up for the loss of REP-1, but REP-2 is lacking in the retina. As a result, photoreceptor cells die, starting with rods. Eventually, the choriocapillaris and pigment epithelium atrophy.

Because the gene is located on the X chromosome, typically only males suffer the full effects. Symptoms usually begin with night blindness in the patient's teenage years, followed by blind spots, then tunnel vision, and eventually complete blindness by the time the patient is in his 50s. Choroideremia affects about 1 in 50,000 people.

For the gene therapy, Thomas L. Edwards, PhD, and colleagues from the University of Oxford and multiple other centers in the United Kingdom delivered nonmutated CHM in an adeno-associated virus (AAV.REP1) through a subfoveal injection into the vicinity of the retinal pigment epithelium and photoreceptor cells.

They treated one eye in each of six patients, leaving the fellow eye as a control. Six months after treatment, all six patients had recovered visual acuity, as reported by Medscape Medical News.

Now, the researchers report on the patients' status 3.5 years after treatment.

Patients 1 and 4 had advanced disease at baseline, with study eyes several lines below normal on the Early Treatment of Diabetic Retinopathy Study (EDTRS) chart.

By 3.5 years, visual acuity in the treated eye of patient 1 had increased by 21 letters (more than four lines) from baseline. In patient 2, it increased 18 letters (more than three lines). Meanwhile, vision in these patients' untreated eyes continued to decline.

The other four patients had good visual acuity at baseline, and therefore less room for improvement. Patient 3 started with a visual acuity of 89 EDTRS letters (20/16) and was able to return to that level after cataract surgery. Improvements in the treated eye showed up on an electrophysiological study.

The visual acuity of the treated eyes in patients 2 and 5 remain close to baseline. Meanwhile, the control eye in patient 2 lost 10 letters, and the control eye of patient 5 lost 11 letters.

In contrast, however, the treated eye of patient 6 had declined by 29 letters and the control eye by 18 letters. This patient received a lower dose of the genes than the other patients in the trial, and the researchers speculate that this could account for the loss of acuity.

Because choroideremia progresses slowly, the effects of the treatment may take years to become fully clear, the researchers note.

In this way, choroideremia differs from Leber's congenital amaurosis, which profoundly affects visual acuity early in life.

In two similar gene therapy treatments for Leber's congenital amaurosis, initial effects were very promising, as reported by Medscape Medical News, but the improvements peaked by 3 years, and photoreceptors appeared to continue degenerating.

Other trials using slightly different transgene designs for Leber's congenital amaurosis are underway.

One reason that treatment for choroideremia might be more successful is that REP-1 is smaller than the analogous protein in Leber's congenital amaurosis, rAAV2-CB-hRPE65 (RPE65), and perhaps easier to produce, Dr Maturi said.

The success of this treatment gives hope that gene therapy can work for other genetic retinal diseases, he continued. "We're all looking forward to a day when we can treat the most common congenital retina diseases: Stargardt's and retinitis pigmentosa."

In the meantime, further research on this treatment for choroideremia could be challenging because it is such a rare disease, he said. It may be hard to find a drug company willing to invest in the large clinical trials normally needed to commercialize a new treatment.

The study was supported by the Wellcome Trust, the UK Department of Health, the Health Foundation, Fight for Sight, the Lanvern Foundation, the Special Trustees of Moorfields Eye Hospital, the Royal College of Surgeons of Edinburgh, the Choroideremia Research Foundation, the National Institute for Health Research Biomedical Research Centres at Oxford University Hospitals, the NHS Foundation, the Moorfields Eye Hospital NHS Foundation Trust, Foundation Fighting Blindness Research Center, Health Innovation Challenge Fund, Servier, ISIS, Nuffield Medical Fellowship, Gift of Sight Appeal, Oxford Biomedical Research Council, FME, NightstaRx, Bayer, RANZCO, Wellcome Trust, and patents in AAV-Rep1 and Vector Administration and Dosing.

N Engl J Med. Published online April 27, 2016. Full text

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