Gene therapy offers treatment for X-linked retinitis pigmentosa

AAV8-RPGR gene therapy for X-linked retinitis pigmentosa showed early responses to treatment at one month with increased retinal sensitivity with retinal toxicity. 

This article was reviewed by Paulo E. Stanga, MD

The results of treatment of X-linked retinitis pigmentosa (XLRP) with AAV8-RPGR gene therapy proved to be early and effective with durable improvements in vision occurring as early as one month following treatment. 

XLRP, a rare disease that comprises 10% to 20% of RP worldwide, affects mostly males, and 70% of the cases are caused by RPGR gene mutations and 60% of those are caused by gene mutations in RPGR-ORF15. In this form of RP, the median age of blindness is 45 years, which is younger than the other forms. 

Disease progression occurs in stages, with nyctalopia manifesting in the early stage, peripheral visual field constriction in the middle stage, and central visual deterioration and visual loss in the end stage, according to Paulo E. Stanga, MD, professor of Ophthalmology and Retinal Regeneration, Manchester Royal Eye Hospital and University of Manchester, London, UK.

The RPGR mutations cause abnormal transport across the cilium, where RPGR is located, and this abnormal transport results in photoreceptor death. 

“Obviously, this leads to loss of retinal sensitivity across the visual field and loss of visual acuity,” he said. 

The treatment that Dr. Stanga and colleagues devised has the goal of correcting the full length of the RPGR-ORF15 mRNA. 

“We aim for yields of high expression levels that are four times higher than the expression levels of the wild-type RPGR,” he explained.

Six-month Phase I results 
Dr. Stanga and colleagues are currently conducting a two-year dose-escalation clinical trial. The study included men who were 18 years and older with genetically confirmed XLRP. All patients had active disease that was visible bilaterally in the maculas. The study included six cohorts, with the following levels of affect vision: 1, better than light perception; 2 and 3, 34 to 73 Early Treatment Diabetic Retinopathy Study (ETDRS) letters; and 4, 5, and 6, greater than 34 ETDRS letters.

The primary endpoint was the incidence of dose-limiting toxicities and treatment-emergent adverse events. The secondary endpoints were the changes in microperimetry, visual stability, and changes in the ellipsoidal zone on spectral-domain optical coherence tomography, Dr. Stanga recounted.

The patients underwent a surgical procedure that included creation of a bleb followed by injection of the virus vector within the bleb.

The investigators evaluated the early effects of changes in the retinal sensitivity in the central retina using microperimetry (Maia, Centervue). The central 16 retinal loci represent 8 degrees of vision; an improvement of five of the central 16 loci equals a 30% improvement in the central visual field. An improvement of 7 dB represents five times greater light sensitivity, he explained.

One month after treatment, Dr. Stanga reported that there was a significant improvement in microperimetry in six of the 12 treated eyes in cohorts 3 to 6 that occurred at one month after vector injection; these cohorts received therapeutic doses. Cohorts 1 and 2, which received subtherapeutic doses, showed no changes.

Cohort 3 showed a mean improvement in the mean retinal sensitivity of 5 to 6 dB in the central 16 retinal loci between the treated and untreated eyes. The improvement became apparent at one month and remained relatively stable at three and six months, Dr. Stanga reported.

According to Dr. Stanga, these changes in retinal sensitivity differed from those observed in untreated eyes in the central 16 retinal loci. The untreated eyes showed decreases in retinal sensitivity over time. 

The microperimetry heat maps also reflected the changes in the treated eyes with enlargement of the sensitive areas. 

The investigators also reported that they also determined that the gene therapy with AAV8-RPGR gene therapy for XLRP was generally well tolerated. 

No patients left the study and no dose-limiting toxicities were readily apparent. 

Transient inflammation developed in the higher cohorts that responded to systemic steroid therapy. Two ocular adverse effects were related to the procedure or drug.
 

Conclusions
“We demonstrated proof of concept with durable dose-related improvements that appeared as early as one month after treatment across multiple microperimetry analyses,” Dr. Stanga concluded. “The preliminary efficacy signals were exhibited in cohorts 3 to 6, which responded to the highest doses.”

Paulo E. Stanga, MD
E: p.stanga@retinaspecialist.co.uk
This article is based on Dr. Stanga's presentation at the American Academy of Ophthalmology 2019 annual meeting. Dr. Stanga has no financial interest in this subject matter.