Gene therapy: Where the action is for retinal diseases

Growth in the clinical and commercial development of gene therapies for retinal degenerative diseases has been explosive over the past decade. The rapid expansion of the field has been led by dramatic vision restoration for virtually blind patients made possible by voretigene neparvovec-rzyl(Luxturna; Spark Therapeutics), which the FDA approved in December 2017. It is the first gene therapy for the eye or any inherited retinal disease to cross the regulatory finish line in the United States. Developed by gene therapy pioneer Jean Bennett, MD, PHD, for children and adults with Leber congenital amaurosis (LCA) or retinitis pigmentosa (RP) caused by biallelic RPE65 mutations, the therapy provided immediate and impressive vision improvements in a phase 1/2 clinical trial at Children’s Hospital of Philadelphia. Those initial results, reported in 2008, sent a strong signal to investigators and biotechnology companies that gene therapy could be a powerful modality for treating retinal diseases.

Now, dozens of companies are in the retinal gene therapy development space and more than 20 clinical trials for genetic therapies are underway for patients with a broad range of retinal degenerative diseases. These include RP, LCA, choroideremia, achromatopsia, and the dry and wet forms of age-related macular degeneration (AMD).

The Foundation Fighting Blindness, the world’s leading private funder of retinal degenerative research, has played a pivotal role in advancing retinal gene therapies into clinical development. As an early funder of the modality for myriad retinal diseases, the foundation began investing in RPE65 gene therapy research back in the mid-1990s and ultimately invested $10 million in the research that eventually led to voretigene neparvovec.

“We were very early adopters, recognizing that the retina was an ideal gene therapy target. It’s a small, accessible piece of tissue, and many conditions that affect the retina are monogenic. We knew that if we could directly address the patient’s mutated gene by augmenting or modifying its activity, we had an excellent opportunity to save and restore vision,” said Benjamin Yerxa, PhD, chief executive officer at the foundation. “Furthermore, we see gene therapy’s potential for gene-agnostic applications such as neuroprotection and optogenetics to help a broad range of patients, regardless of the mutated gene causing their vision loss.”

The foundation currently funds a broad range of gene therapies and other treatment modalities at both early and late stages of development. Its RD (Retinal Degeneration) Fund, a venture philanthropy fund with nearly $120 million in commitments, was launched in 2018 to help investigators and start-up companies move their emerging therapies into and through early-stage clinical trials. The fund’s goal is to attract additional investments from pharmaceutical and biotechnology companies to fund the more expensive, late-stage trial phases. Furthermore, all returns on the fund’s investments are put back into the foundation to support additional research and investments.

“The ultimate goal of the RD Fund is to get more treatments across the finish line and out to patients. We can’t afford to fund late-stage clinical research, which often costs a hundredmillion dollars or more, but we can afford the earlier-stage research to attract those major investments from biotechs and big pharma,” said Yerxa.

In fall 2021, the RD Fund took the bold step of launching its own company, Opus Genetics, to develop gene therapies for orphan retinal diseases, those rare conditions that weren’t being addressed by other companies. Opus’ $19 million in seed financing included investments from the Manning Family Foundation and Bios Partners. Its first 3 targets are for LCA caused by mutations in LCA5, RDH12, and NMNAT1. The LCA5 and RDH12 therapies were developed preclinically by Opus cofounder Bennett and licensed from the University of Pennsylvania. The NMNAT1 treatment was developed in the laboratory by cofounder Eric A. Pierce, MD, PhD, and licensed from Harvard Medical School’s Massachusetts Eye and Ear. Opus plans to launch a clinical trial for LCA5 by the end of 2022. In April 2022, the company signed a collaboration agreement with Resilience to provide manufacturing services for its gene therapy pipeline.

In October 2020, the RD Fund realized its first financial win when Novartis acquired Vedere Bio for around $280 million. In 2019, the fund had helped launch Vedere Bio to advance an optogenetic therapy developed by its scientific cofounders John G. Flannery, PhD, and Ehud Isacoff, PhD, from the University of California, Berkeley. The investigators’ approach––a gene-agnostic gene therapy––provides potential vision restoration for patients who have lost all their photoreceptors to a condition such as RP by delivering a gene that expresses a light-sensing green cone opsin in surviving ganglion cells. In essence, the treatment enables ganglion cells to work like a back-up system for lost photoreceptors. The approach holds promise for restoring vision for patients who are completely or nearly blind, regardless of the mutation causing their disease. A new incarnation of the company, Vedere Bio II, was subsequently launched after the Novartis acquisition to continue development of other retinal gene therapies.

Also in 2020, the RD Fund invested in the gene therapy start-up Atsena Therapeutics, which reported early, encouraging vision improvements for 3 patients in a phase 1/2 clinical trial for its LCA (GUCY2D mutations) gene therapy. Cofounded by Shannon E. Boye, PhD, and Sanford L. Boye, MS, both of the University of Florida in Gainesville, Atsena also has preclinical gene therapy programs for X-linked retinoschisis and Usher syndrome type 1B.

SparingVision, another RD Fund investment, is planning to launch a clinical trial in 2022 for its gene-agnostic, cone-preserving therapy for patients with RP, Usher syndrome, and related conditions. Nearly 2 decades ago, José-Alain Sahel, MD, and Thierry Léveillard, PhD, investigators from the Institut de la Vision in Paris, France, identified a protein secreted by rod photoreceptors that is critical to the survival of cones. Aptly named rod-derived cone-viability factor, it is the protein expressed by SparingVision’s cone-preserving gene therapy. The company is also developing a gene therapy that restores light sensitivity to cones that have lost their ability to process light due to advanced forms of RP, Usher syndrome, and related diseases.

The RD Fund’s other gene-related therapy investments include SalioGen Therapeutics, whose Saliogase technology seamlessly inserts new DNA of any size (eg, the Stargardt disease gene ABCA4) into precise, defined genomic locations. The fund also invests in ProQR Therapeutics, which has an RNA therapy in a phase 2/3 clinical trial for individuals with Usher syndrome 2A and nonsyndromic RP caused by mutations in exon 13 of the USH2A gene.

“We are off to a great start with our investments and working to continue to expand our portfolio with the strategy of investing in strong science being developed by well-managed companies,” said Yerxa. “I think our coinvestors recognize and appreciate our commitment to making every shot on goal really count.”