Genetically Engineered Treatment for Blindness Shows Early Promise in Small Study

A majority of patients with advanced retinitis pigmentosa (RP) showed preliminary evidence of improved light sensitivity with engineered genes encoding for a light-sensing protein, a small preliminary trial showed.

Seven of 10 patients had increased light sensitivity after optogenetics treatment, aided by use of light-stimulating goggles. The improvement was clinically meaningful in six cases. Ocular adverse events (AEs) were common, with 34 events occurring in nine of the 10 patients, including one severe AE.

The modest dataset suggests the treatment, combined with the goggles, is safe and warrants additional studies to assess safety and efficacy, reported José-Alain Sahel, MD, of the University of Pittsburgh School of Medicine, and colleagues in the New England Journal of Medicine.

“These results show that even in people with profound vision loss, the visual system retains a remarkable capacity to process new information,” Sahel said in a press release. “Potentially, the approach could also help patients with other blinding diseases in which the eye’s light-sensing cells have been lost, but other retinal cells, especially retinal ganglion cells, remain viable. Many of these patients currently have few or no treatment options.”

Despite the small numbers and preliminary nature of the study, the findings offer some encouragement for a patient population that has no effective options, said Richard Rosen, MD, of the Icahn School of Medicine at Mount Sinai in New York City.

“I see a fair number of these patients and we have nothing to offer them,” Rosen, who was not involved in the study, told MedPage Today. “I think this is something to look forward to for these patients, potentially a useful approach.”

Other approaches that have used electrical stimulation to treat RP generated a lot of excitement early on but have yet to make much of an impact, he added.

“I think this is even more exciting because it’s a more permanent kind of fix. It just needs refining,” said Rosen.

RP destroys the rods and cones, the primary light-sensing photoreceptor cells in the retina. Optogenetics involves use of an adeno-associated virus vector to deliver genetically engineered genes that encode for the light-sensing protein ChrimsonR into retinal ganglion cells, which are not light sensing. The objective is to induce light sensitivity into the transfected cells.

To activate the protein, the patient wears specialized goggles that have a built-in camera that sends visual information to a portable processor, which converts the information into light patterns of a specific wavelength designed to activate the protein. A projector in the goggles transmits the light patterns back to the eye.

RP is not a single condition but encompasses more than 100 different types of defects, Rosen noted. Whereas conventional gene therapy targets one type of defect, optogenetics offers the advantage of being an “agnostic” treatment that can be applied across the range of defects. The objective remains the same: to induce light sensitivity in cells that normally are not light sensitive.

Investigators previously reported positive results from the first patient treated with optogenetic therapy. Following the treatment, the patient “perceived, located, counted, and touched different objects using the vector-treated eye alone while wearing the goggles.” Before treatment, the patient “could not visually detect any objects before injection with or without the goggles.”

The current report included 10 patients with “profound visual impairment in both eyes” from RP, meeting generally accepted criteria for legal blindness. The optogenetic therapy consisted of a single intravitreal injection in the eye with the worst vision. The primary endpoint was safety, and the key secondary endpoint was change in light sensitivity measured by full-field stimulus threshold (FST) testing. Clinically meaningful improvement in FST (based on literature review and not prespecified in the protocol) was defined as a decrease of at least 0.6 log units (an increase in light sensitivity by a factor of approximately 4).

One patient withdrew from the study 6 months after injection, and a second patient withdrew after 2.5 years of follow-up. Four patients completed the planned 5 years of follow-up, and the remaining four had completed 2 to 4.5 years of follow-up at data analysis.

Of the 34 documented ocular AEs, 23 were considered mild and 10 moderate. The one serious AE was transient occlusion of the central retinal artery, occurring immediately after injection, manifesting as amaurosis fugax. The event resolved within minutes after instillation of apraclonidine (Iopidine).

Additionally, 70 systemic AEs occurred in the 10 study participants, 39 considered mild, 25 moderate, and six severe. No systemic AE was considered related to the treatment or injection procedure.

FST testing showed that light sensitivity improved after treatment in seven of 10 participants, increasing by a factor of 2.0 to 62.3 from baseline. Clinically meaningful improvement occurred in six patients, and three had no change or a decrease in light sensitivity (factor change ranging from 0.4 to 1.0).

Investigators evaluated visual performance in the treated eye with and without the goggles and with a patch over the untreated eye. Results with the goggles varied considerably. Four of eight participants who completed three visual behavioral tests performed better with the goggles and were subjectively considered as having a response. Participants who did not respond showed no consistent improvement in the behavioral visual tests throughout follow-up.