Another gene therapy for a central nervous system disorder has posted positive results. The Phase 1/2 trial enrolled 18 men with X-linked retinitis pigmentosa (RP), a disease of retinal degeneration that leads to blindness. Robert MacLaren of the University of Oxford led the study, published February 24 in Nature Medicine.

  • Phase 1/2 gene therapy trial for retinitis pigmentosa met safety endpoint.
  • Seven of 18 patients were able to see better.
  • Mild inflammation in the eye cropped up at highest doses.

The dose-escalation trial tested six doses; the therapy consisted of an adeno-associated virus 8 expressing a normal copy of the RP GTPase gene. Seven patients saw improvements in their vision that endured for the six-month duration of the trial. Inflammation within the eye cropped up at the higher doses, which may have temporarily blurred therapeutic effects in some patients. 

Interest in using gene-based therapy for AD and other neurodegenerative disorders has grown ever since such a therapy was approved for treating spinal muscular atrophy (SMA) in babies and toddlers, and the field is now looking to learn from trials of other nervous system disorders (Nov 2019 newsDec 2019 news). 

X-linked RP is caused by mutations in the RP GTPase regulator (RPGR) gene. The mutations trigger degeneration of photoreceptors starting in childhood. No treatments exist. Recent approval of a gene therapy for another retinal disorder—RPE65-related retinal degeneration—suggests retinal gene therapy could work (Russell et al., 2017). 

However, the RPGR gene has confounded scientists, as it contains a repetitive, purine-rich stretch that undergoes alternative splicing. Tinkering with the sequence has boosted fidelity and stability of the gene, and conferred therapeutic benefits in animal models of the disease (Fischer et al., 2017). 

In this trial, each of the 18 men, who were between 22 and 50 years old, had severe retinal degeneration. They were recruited in six cohorts of three patients each, who received increasing doses of the viral therapy. The participants received an injection of the virus into their subretinal space; they were then monitored for safety—the trial’s primary outcome—and tested for vision and retinal sensitivity for six months.

Across the cohorts, 55 adverse events occurred, all mild. Seven out of nine patients on the three highest doses experienced mild retinal inflammation, which was corrected by oral corticosteroids. In all, the trial met its primary safety endpoint.

Seven out of 12 patients receiving one of the top four doses had visual gains in the treated eye. This was gauged by retinal microperimetry, a map of the quality of light perceived across the retina. The improvements started at one month and continued at the six-month follow-up. The researchers proposed that inflammation in the top three dose cohorts may have offset visual improvements in some patients.

The trial was not designed to draw conclusions about efficacy. The researchers speculated that the therapy’s effectiveness will boil down to the stage of retinal degeneration, vector dose, and any interfering effects of inflammation. The second phase of the study will compare two doses to placebo.

Though the eyes are not strictly the brain, retinal therapy can be considered as part of the revitalization of gene-therapy approaches for neurodegenerative diseases. AAV-based expression of survival motor neuron 1 has improved life for those with SMA, but the tricky aspects of RPGE gene expression, and the inflammatory response that cropped up at higher doses, point to potential challenges other gene therapies may have to overcome (Nov 2016 news; Mendell et al., 2017).—Jessica Shugart


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News Citations

  1. Time to Try Again: Gene-Based Therapy for Neurodegeneration
  2. Lysosomal Diseases: Stepping Stones to Gene Therapy for Alzheimer’s?
  3. Positive Trials of Spinal Muscular Atrophy Bode Well for Antisense Approach

Paper Citations

  1. . Efficacy and safety of voretigene neparvovec (AAV2-hRPE65v2) in patients with RPE65-mediated inherited retinal dystrophy: a randomised, controlled, open-label, phase 3 trial. Lancet. 2017 Aug 26;390(10097):849-860. Epub 2017 Jul 14 PubMed.
  2. . Codon-Optimized RPGR Improves Stability and Efficacy of AAV8 Gene Therapy in Two Mouse Models of X-Linked Retinitis Pigmentosa. Mol Ther. 2017 Aug 2;25(8):1854-1865. Epub 2017 May 24 PubMed.
  3. . Single-Dose Gene-Replacement Therapy for Spinal Muscular Atrophy. N Engl J Med. 2017 Nov 2;377(18):1713-1722. PubMed.

External Citations

  1. dose-escalation trial

Further Reading

No Available Further Reading

Primary Papers

  1. . Initial results from a first-in-human gene therapy trial on X-linked retinitis pigmentosa caused by mutations in RPGR. Nat Med. 2020 Mar;26(3):354-359. Epub 2020 Feb 24 PubMed.