A computer rendering of tweezers holding a chunk of a strand of DNA.

Clinical Challenges: Gene Replacement Therapy for Hereditary Retinal Disorders

Hereditary retinal disorders (IRDs) – a group of genetically variable disorders that lead to severe visual impairment or blindness – have long been considered incurable.

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

“The types of treatments under investigation 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 RPE65, a protein that patients with biallelic RPE65 mutations are lacking,” said Christina Weng, MD, MBA, of the Baylor College of Medicine and the Cullen Eye Institute in Houston. MedPage today† “Other treatments appear to affect the visual modulation cycle that is disrupted in these diseases. Stem cell and regenerative therapies are being explored, although they have not yet been overwhelmingly successful.”

While gene therapy is not a cure for IRDs, it provides a way to control 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 repeated interventions, unlike some therapies for retinal disorders 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 reviewresearchers described “five different approaches to gene-based therapy that have the potential to treat the full spectrum of IRDs”:

  • Gene replacement using AAV and non-viral 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 splice modification
  • Optogenetic approaches that “aimed at replacing the function of native retinal photoreceptors by manipulating other retinal cell types to be capable of phototransduction”

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

  • Stargardt’s disease (ABCA4
  • achromatopsia (CNGA3CNGB3
  • 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 standpoint, there are also promising avenues being explored for age-related macular degeneration,” she said.

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

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

In a 2021 discussionresearchers noted that innovative approaches are being used for genes that are too large to fit into 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 is also intriguing “because the gene-agnostic approach would be applicable to multiple inherited retinal disorders rather than just a small number with a specific mutation,” Weng said. “In this form of treatment, gene therapy essentially converts certain retinal cells into light-sensitive cells with a photoreceptor-like function.”

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

Results of the phase IIb trial are expected in 2023, and the same therapy is being assessed in a phase II trial for Stargardt’s disease, Weng said.

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

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    Kate Kneisel is a freelance medical journalist based in Belleville, Ontario.


Weng reported relationships with Alcon, Alimera Sciences, Allergan/AbbVie, the Dutch Ophthalmic Research Center, Genentech, Novartis, Regeneron and Regenxbio.

Qian reported consulting work for AbbVie, Bausch & Lomb, Bayer, Boehringer Ingelheim, Janssen, Novartis and Roche.

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