About 10 years ago, an ophthalmology resident described inherited retinal dystrophies (IRDs) to me as a “sleepy field with minimal interventions.” While potentially true at that time, there has been an exponential growth phase of clinical trials and therapeutic possibilities over the last half decade, which has catapulted IRDs to one of the most exciting fields in all of ophthalmology. To understand IRDs, retina specialists need to master core concepts in genetics, molecular biology, and clinical trial design. In this issue, I have asked 2 experts in the field, Peter Zhao, MD, and his mentor Thiran Jayasundera, MD, to provide us an overview on recent developments. The list is far from exhaustive but hopefully provides a framework for treating (or curing) IRDs one at a time.

New Areas of Investigation in IRD

Peter Y. Zhao, MD, and Thiran Jayasundera, MD, MS

There have been significant advances in the understanding of the genetic basis of IRDs over the past several decades, and the field of IRDs is poised for further leaps that may lead to therapeutic options. In 2017, voretigene neparvovec-rzyl (Luxturna; Spark Therapeutics) became the first FDA-approved gene therapy for IRDs caused by variants in the RPE65 gene.¹ A number of ongoing clinical trials could lead to additional therapies for IRDs over the next several years.

A variety of treatment approaches are needed for IRDs, because patients may seek care at different stages of disease. Early in the disease course, a sensible approach would be to slow or stop the retinal degeneration. To slow or stop degeneration, pharmacotherapies that modulate the underlying disease pathophysiology or gene therapies that restore a loss of protein function are being investigated. In contrast, a patient who seeks care late in the disease course might already have poor vision, and a different approach would be required to restore visual function. To restore function, other approaches such as optogenetics, stem cell therapy, or retinal prostheses are being investigated.

ABCA4 AND STARGARDT DISEASE

Stargardt disease is an autosomal recessive macular dystrophy characterized by macular atrophy and progressive loss of central visual acuity. Autosomal dominant Stargardt-like macular dystrophies also exist, but the classic autosomal recessive form is called Stargardt disease. The disease is caused by variants in the ABCA4 gene, a transporter protein that shuttles vitamin A out of the photoreceptor outer segments.² When ABCA4 function is reduced, toxic vitamin A byproducts accumulate in the outer segments that are engulfed by the retinal pigment epithelium (RPE). The toxic byproducts lead to RPE and photoreceptor degeneration.

One approach to slowing the progression of Stargardt disease is slowing down the visual cycle by inhibiting RPE65, a protein in the RPE that processes vitamin A for photoreceptor use. Emixustat is an oral small molecule inhibitor of RPE65 developed by Kubota Vision. A phase 2a study confirmed the biologic activity of emixustat, which suppresses the rod photoreceptor B-wave recovery rate on electroretinography, a surrogate marker for slowing of the visual cycle.³ Two adverse effects related to the drug’s mechanism of action include chromatopsia, or a dark tint to vision, and delayed dark adaptation. These effects resolved 1 to 2 weeks after stopping the drug. The SeaSTAR phase 3 multicenter randomized controlled trial with 194 patients is ongoing and expected to conclude in June 2022.⁴

USH2A AND USHER SYNDROME TYPE 2A

Usher syndrome type 2A is an autosomal recessive disease characterized by varying degrees of vision and hearing impairment. The ocular manifestation of the disease is retinitis pigmentosa (RP), with bone spicules, waxy pallor of the optic disc, and vascular attenuation. Night and peripheral vision are impaired early in the disease course, followed by gradual loss of central visual acuity as the degeneration progresses into the fovea. Cystoid macular edema can also develop, leading to earlier loss of central visual acuity. The disease is caused by variants in the USH2A gene that encodes usherin, a basement membrane–associated protein produced in the inner ear and the retina.⁵

Ultevursen (ProQR Therapeutics) is an anti-sense oligonucleotide that induces skipping of exon 13 during protein production, leading to a more functional protein.⁶ ProQR Therapeutics announced positive results from the STELLAR phase 1/2 trial of intravitreal injection of ultevursen demonstrating improvements in best-corrected visual acuity and retinal sensitivity. Based on these positive results, the company launched parallel phase 2/3 trials in December 2021: the CELESTE trial⁷ for early-to-moderate disease, and the SIRIUS trial⁸ for advanced disease. Each trial will enroll approximately 100 adult patients who specifically have disease-causing variants in exon 13 of the USH2A gene (approximately one-third of affected patients).

RPGR AND X-LINKED RP

The RPGR gene is located on the X-chromosome, and variants in RPGR are responsible for approximately 75% of cases of X-linked RP, or 10% of all cases of RP. Interestingly, RPGR also causes a proportion of cases of cone-rod dystrophy and cone dystrophy. The RPGR gene encodes a protein in the connecting cilium that bridges the inner and outer segments of photoreceptors.⁹

Two groups are pursuing vitrectomy with subretinal gene therapy to treat the disease: the Applied Genetic Technologies Corporation (AGTC) using an adeno-associated virus 2 (AAV2) vector (AGTC-501),¹⁰ and MeiraGTx/Janssen Pharmaceuticals using an AAV5 vector (MGT-009). The goal of subretinal gene therapy is to deliver a normal copy of the RPGR gene to photoreceptors, restoring functional protein expression.

For AGTC-501, the phase 1/2 trial demonstrated safety and potential improvements in visual acuity and retinal sensitivity. The AGTC SKYLINE¹¹ phase 2 follow-up and VISTA¹² phase 2/3 trials are in progress with an anticipated 108 participants across the trials. The 12-month results from SKYLINE and interim results from VISTA are expected in 2023.

For MGT-009, the phase 1/2 trial demonstrated stability or improvements in retinal sensitivity, and improvements in vision-guided mobility. The LUMEOS¹³ phase 3 trial is recruiting 66 participants and will follow patients for 52 weeks after treatment.

OPTOGENETICS AND ADVANCED RETINAL DEGENERATIONS

In advanced disease, therapies to restore vision are preferred to those that slow or stop degeneration. Approaches to restore function include retinal prosthesis, stem cell therapy, and optogenetics. The Argus retinal prosthesis (Second Sight Medical) was approved to address this area of need, but production was discontinued in 2020.

Another innovative method of restoring vision is optogenetics. In the late stages of diseases such as RP, there is extensive loss of photoreceptors, but other cells, such as retinal ganglion cells, remain alive. Optogenetic vision restoration uses gene therapy to deliver a new light-sensing protein into the retinal ganglion cells. Gensight Biologics is leading the way with PIONEER,¹⁴ a phase 1/2 trial examining intravitreal delivery of the channelrhodopsin ChrimsonR to retinal ganglion cells via an AAV2 vector.¹⁵ The first patient treated as part of this study recovered the ability to perceive, locate, count, and touch objects with the aid of engineered goggles. The trial expects to enroll approximately 15 participants with features of advanced RP and visual acuity between counting fingers and light perception. RP

REFERENCES

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7. Study to evaluate the efficacy safety and tolerability of QR-421a in subjects with RP due to mutations in exon 13 of the USH2A gene with early to moderate vision loss (Celeste). Clinicaltrials.gov identifier: NCT05176717. Updated February 24, 2022. Accessed March 15, 2022. https://clinicaltrials.gov/ct2/show/NCT05176717
8. Study to evaluate the efficacy safety and tolerability of QR-421a in subjects with RP due to mutations in exon 13 of the USH2A gene with advanced vision loss (Sirius). Clinicaltrials.gov identifier: NCT05158296. Updated February 24, 2022. Accessed March 15, 2022. https://clinicaltrials.gov/ct2/show/NCT05158296
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10. Song C, Dufour VL, Cideciyan AV, et al. Dose range finding studies with two RPGR transgenes in a canine model of x-linked retinitis pigmentosa treated with subretinal gene therapy. Hum Gene Ther. 2020;31(13-14):743-755. doi:10.1089/hum.2019.337
11. Safety and efficacy of rAAV2tYF-GRK1-RPGR in subjects with X-linked retinitis pigmentosa caused by RPGR mutations. Clinicaltrials.gov identifier: NCT03316560. Updated May 21, 2021. Accessed March 18, 2022. https://clinicaltrials.gov/ct2/show/NCT03316560
12. A clinical trial evaluating the safety and efficacy of a single subretinal injection of AGTC-501 in participants with X-linked retinitis pigmentosa caused by RPGR mutations. Clinicaltrials.gov identifier: NCT04850118. Updated May 21, 2021. Accessed March 15, 2022. https://clinicaltrials.gov/ct2/show/NCT04850118
13. Gene therapy trial for the treatment of X-linked retinitis pigmentosa associated with variants in the RPGR gene. Clinicaltrials.gov identifier: NCT04671433. Updated September 27, 2021. Accessed March 15, 2022. https://clinicaltrials.gov/ct2/show/NCT04671433
14. Dose-escalation study to evaluate the safety and tolerability of GS030 in subjects with retinitis pigmentosa (PIONEER). Clinicaltrials.gov identifier: NCT03326336. Updated February 4, 2021. Accessed March 15, 2022. https://clinicaltrials.gov/ct2/show/NCT03326336
15. Sahel JA, Boulanger-Scemama E, Pagot C, et al. Partial recovery of visual function in a blind patient after optogenetic therapy. Nat Med. 2021;27(7):1223-1229. doi:10.1038/s41591-021-01351-4