Editors' ChoiceGene Therapy

Hope on the horizon for inherited blindness

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Science Translational Medicine  18 Mar 2020:
Vol. 12, Issue 535, eabb2772
DOI: 10.1126/scitranslmed.abb2772


In a clinical trial, gene therapy for X-linked retinitis pigmentosa improved vision.

X-linked retinitis pigmentosa due to mutations in the RPGR gene is a common and severe cause of genetic vision impairment, ultimately leaving young males legally blind. The disease results in the degeneration of rod and cone photoreceptors leading to progressively constricting visual fields until only a small island of vision remains. RPGR-associated retinitis pigmentosa is an unmet medical need without any specific therapy.

Cehajic-Kapetanovic et al. recently published long-awaited results from a gene therapy clinical trial in men with X-linked retinitis pigmentosa using a gene addition (also called “gene replacement”) strategy. The team developed an adeno-associated virus vector carrying the normal coding sequence of RPGR and optimized it in mouse models before translating it to humans. In the current Phase 1/2 dose-escalation study, 18 patients were injected into one eye and followed up to six months. The primary aim was to test safety in patients with advanced RPGR-retinitis pigmentosa. Preliminary efficacy was also assayed using microperimetry, a form of visual field testing that allows measuring of retinal sensitivity in injected and noninjected areas. Overall, the treatment was well tolerated, with only one patient experiencing transient regression of retinal function. Retinal sensitivity did not improve in patients injected with low vector dose, but enlargement of the visually sensitive area was seen in seven out of 12 patients in the mid- and high-dose cohorts. These patients subjectively confirmed that the intervention improved their ability to see.

These results are still preliminary, and continued assessment is necessary to precisely determine visual outcome. It is not entirely clear what benefit gene therapy will ultimately bring to the patients—will it slow the progression of the disease or will it actually improve vision long term? This is a critical question that must be taken into consideration before designing subsequent clinical trials, as the outcome measures would be different depending on the answer. Nevertheless, early data suggests that gene therapy can open up the small window through which patients perceive the outside world. Treating ophthalmologists can finally tell these patients—“there is hope on the horizon in your case.”

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