Novel gene therapy offers vision gains for X-linked retinitis pigmentosa


Sub-retinal injection of adeno-associated virus leads to visual acuity gains.

Reviewed by Dr Robert A. Sisk.

Novel gene therapy offers vision gains for X-linked retinitis pigmentosa

AGTC-501 (Applied Genetic Technologies Corporation), a novel gene therapy in development for the potential treatment of X-linked retinitis pigmentosa (RP), has shown an acceptable safety profile and visual function improvements at higher doses, according to Dr Robert A. Sisk, director of pediatric vitreoretinal surgery and director of ophthalmic genetics at Cincinnati Children’s Hospital and the Cincinnati Eye Institute, Ohio, United States.

Patients with X-linked RP, an inherited retinal disease that begins in childhood, experience night blindness, progressive loss of peripheral vision and eventual loss of central vision. Affected patients currently have access to only one approved treatment, voretigene neparvovec-rzyl (Luxturna, Spark Therapeutics) for RPE65, which represents about 1% of RP.

AGTC-501 trial

An early-stage gene therapy study in X-linked retinitis pigmentosa patients led to improvements in visual acuity, microperimetry sensitivity and foveal ellipsoidal zone status.

Dr Sisk outlined the safety and efficacy findings of a Phase 1/2 study of AGTC-501, a recombinant adeno-associated virus (AAV) 2 vector, for X-linked RP resulting from mutations in the RPGR gene, which accounts for 10% of RP cases. This study was a 12-month open-label, dose-escalation trial that included 29 male patients aged 6 years and older with the RPGR mutation.

All patients were treated with one sub-retinal injection in the study eye. The first nine patients received peripheral retinal injections as part of a safety assessment, which was the primary outcome, and the rest of the patients were treated centrally.

Dr Sisk stated that the safety assessment also included immunological responses to the AAV capsid and the RPGR proteins expressed. Key secondary outcomes included visual function, measured by microperimetry (Macular Integrity Assessment), and retinal structure status, seen on optical coherence tomography (OCT).

There were no serious adverse events related to the treatment. The initial surgical approach resulted in four peripheral retinal detachments related to dosing targeting the peripheral retina. The detachments did not occur when the central retina was targeted.

Affected paitents with X-linked retinitis pigmentosa currently have access to only one approved treatment.

Grade 1 to 2 intraocular inflammation developed in about 20% (5/29) of patients, but all cases were reported as resolved. About one-third of the patients had intraocular pressure (IOP) elevations related to corticosteroid use, and all have resolved without IOP-related morbidities. The immunological results did not suggest safety concerns.

Regarding vision, in the 20 patients who received injections targeting the central retina, Dr Sisk noted that “the mean visual acuity improved about five letters compared [with] the untreated fellow eyes”.

Dr Sisk reported that the microperimetry sensitivity improved at Month 12 in all centrally dosed patients across the central 36 points, which corresponds to the most anatomically and functionally intact areas in the patient population. He also noted that the US Food and Drug Administration (FDA) has accepted a change of seven or more decibels in five or more loci in the central microperimetry as clinically meaningful.

During the course of the study, the investigators observed that patients without foveal ellipsoid zone (EZ) integrity before the treatment did not have improved microperimetry. When these patients were excluded from analysis, 50% of patients were responders to treatment. Another two patients also had significant improvements in microperimetry compared with the untreated fellow eye.

An analysis based on the status of the macular EZ showed that seven of the 20 patients who were centrally treated had no EZ before or after the AGTC-501 injection. In the 13 patients with a macular EZ at baseline, nine had recovery of the EZ 3–6 months after treatment, and six of the nine had an improved EZ at 12–18 months.

In the other four of the 13 eyes with a macular EZ, all had incomplete EZ recovery at 12 months. Dr Sisk reported positive associations between anatomical improvements in the EZ band and functional microperimetry sensitivities.

Optimising outcomes

In addition to avoiding treatment targeting the peripheral retina, patient selection is paramount to achieve the best results. “Advanced disease with absence of baseline microperimetry or a foveal EZ line precluded meaningful microperimetry or visual benefits,” Dr Sisk said.

Clinical trials of AGTC-501 for the potential treatment of X-linked RP are continuing. The Skyline trial is an expansion of this Phase 1/2 clinical trial, and the Vista trial is a Phase 2/3 safety and efficacy clinical trial.

“The 12-month results of the study of AGTC-501 to treat X-linked RP showed acceptable safety outcomes and vision and microperimetry improvements at higher doses,” Dr Sisk said. “In addition, we observed an encouraging anatomical correlate of EZ improvement.”

Robert Sisk, MD, FACS
This article is adapted from Dr Sisk’s presentation at the American Academy of Ophthalmology 2021 annual meeting, New Orleans, Louisiana, US. Dr Sisk is a consultant to AGTC.
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