Clinical Challenges: Gene Replacement Therapy for Inherited Retinal Diseases

Inherited retinal diseases (IRDs) — a group of genetically variable disorders that result in serious visual impairment or blindness — have long been considered incurable.

Research advances over the past 20 years have allowed for the identification of more than 260 genetic mutations associated with IRDs, and studies of multiple gene replacement therapies hoped to slow disease progression and potentially restore some degree of visual function are underway.

“The types of treatments being explored include monogenetic gene therapies, which target the mutated gene and replace or correct it; for example, our first and only FDA-approved drug, voretigene neparvovec-rzyl, encodes for RPE65, a protein which patients with biallelic RPE65 mutations are missing,” Christina Weng, MD, MBA, of Baylor College of Medicine and the Cullen Eye Institute in Houston, told MedPage Today. “Other treatments look to affect the visual modulation cycle that is disrupted in these diseases. Stem cell and regenerative therapies are being explored, although they have not been overwhelmingly successful yet.”

While gene therapy is not a cure for IRDs, it offers a means of controlling disease progression by treating the faulty gene that causes the disease. That means it is given as a one-time therapy with no need for recurrent interventions, unlike some retinal disease therapies that require direct injections as often as every 3 months. Currently, clinical trials in IRDs are focused on adeno-associated virus (AAV)-based approaches requiring subretinal injection.

In a recent review, researchers described “five distinct approaches to gene-based therapy that have the potential to treat the full spectrum of IRDs”:

• Gene replacement using AAV and nonviral delivery vectors
• Genome editing via the CRISPR/Cas9 system
• RNA editing by endogenous and exogenous ADAR enzymes
• mRNA targeting with antisense oligonucleotides (ASOs) for gene knockdown and splicing modification
• Optogenetic approaches that “aim to replace the function of native retinal photoreceptors by engineering other retinal cell types to become capable of phototransduction”

According to Cynthia Qian, MD, of the University of Montreal, the following IRDs and genetic mutations are the most promising gene therapy candidates:

• Stargardt disease (ABCA4)
• Achromatopsia (CNGA3, CNGB3)
• Usher syndrome (MYO7A)
• Choroideremia (CHM)
• Leber congenital amaurosis (CEP290)
• X-linked retinitis pigmentosa (RPGR)
• X-linked retinoschisis (RS1)
• Leber hereditary optic neuropathy (ND4)

“From a polygenic disease point of view, there are also promising avenues under investigation for age-related macular degeneration,” she said.

“One of our dry macular degeneration drug candidates, avacincaptad pegol (a complement factor C5 inhibitor) is being studied in the STAR study by Iveric Bio for patients with autosomal recessive Stargardt disease 1 (STGD1),” Weng noted. “And a phase II study, TEASE, sponsored by Alkeus is exploring the long-term safety and tolerability of ALK-001 in patients with Stargardt disease.”

In addition, Applied Genetic Technologies Corporation has an ongoing phase I/II study called SKYLINE that is studying a subretinal gene therapy called AGTC-501 for patients with X-linked retinitis pigmentosa with an RPGR mutation, Weng added. “Interim results announced in May 2021 demonstrated that at 12 months, 50% of patients receiving the high dose showed a positive response to treatment based on visual sensitivity, with some even experiencing improvement in visual acuity.”

In a 2021 discussion, researchers noted that innovative approaches are being used for genes that are too big to fit within the AAV delivery vector used with the RPE65 gene, adding that ASOs are being investigated in clinical trials for patients with Usher syndrome and retinitis pigmentosa.

Optogenetics are also intriguing “because its gene-agnostic approach would allow applicability to multiple inherited retinal diseases instead of just a small number with a specific mutation,” Weng said. “In this form of treatment, gene therapy essentially converts certain retinal cells into light-sensing cells with a photoreceptor-like function.”

Nanoscope recently concluded enrollment in their phase IIb optogenetic gene therapy trial for retinitis pigmentosa, she added. “The preceding phase I/IIa trial enrolled 11 patients [with retinitis pigmentosa] and showed that MCO-010 was well tolerated and improved functional vision in patients with advanced disease. Additionally, this therapy is given as a single intravitreal injection that can be administered in the office.”

The phase IIb study results are expected in 2023, and the same therapy is being assessed in a phase II trial for Stargardt disease, Weng said.

The insidious nature of IRDs means that the structural changes they cause may be very subtle early in the disease course, and will become easier to measure over the years as the disease progresses, making functional assessment of clinical outcomes for IRD therapies challenging.