Clinical Challenges: Gene Replacement Therapy for Inherited Retinal Diseases

Inherited retinal diseases (IRDs) – a group of genetically variable disorders that cause severe visual impairment or blindness – have long been thought to be incurable.

Advances in research over the past 20 years have identified more than 260 genetic mutations associated with IRDs, and studies of multiple gene replacement therapies that hoped to slow disease progression and potentially restore some degree of visual function are in progress.

“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, codes for RPE65, a protein that patients with biallelic RPE65 mutations are missing,” said Christina Weng, MD, MBA, of Baylor College of Medicine and the Cullen Eye Institute in Houston. MedPage today. “Other treatments seek to affect the cycle of visual modulation that is disrupted in these diseases. Stem cell and regenerative therapies are being investigated, although they have not yet been successful.”

Although gene therapy is not a cure for IRDs, it offers a way to control the progression of the disease by treating the faulty gene that causes the disease. This means that it is given as a single treatment without requiring recurrent procedures, unlike some retinal disease treatments which 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 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
  • Targeting mRNA with antisense oligonucleotides (ASO) for gene silencing and splicing modification
  • Optogenetic approaches that “aim to override 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, IRDs and the following genetic mutations are the most promising candidates for gene therapy:

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

“From a polygenic disease perspective, there are also promising avenues being investigated 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 Stargardt’s disease recessive 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.”

Additionally, Applied Genetic Technologies Corporation has an ongoing Phase I/II study called SKYLINE that is investigating a subretinal gene therapy called AGTC-501 for patients with X-linked retinitis pigmentosa with a 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 discussion in 2021, researchers noted that innovative approaches are used for genes too large to fit in the AAV delivery vector used with the RPE65 gene, adding that ASOs are being studied in clinical trials for patients with Usher syndrome and retinitis pigmentosa.

Optogenetics is also intriguing “because its gene-independent approach would allow applicability to multiple inherited retinal diseases instead of a few with one specific mutation,” Weng said. “In this form of treatment, gene therapy essentially converts certain retinal cells into light-sensitive cells with photoreceptor-like function.”

Nanoscope recently completed enrollment in its Phase IIb optogenetic gene therapy trial for retinitis pigmentosa, she added. “The previous phase I/IIa trial recruited 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 delivered as a single intravitreal injection that can be administered in the office. »

Results from the Phase IIb study are expected in 2023, and the same therapy is being evaluated in a Phase II trial for Stargardt disease, Weng said.

The insidious nature of IRDs means that the structural changes they cause can be very subtle early in the course of the disease and will become easier to measure over the years as the disease progresses, making it difficult to functional evaluation of the clinical results of IRD therapies.

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


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

Qian has worked as a consultant for AbbVie, Bausch & Lomb, Bayer, Boehringer Ingelheim, Janssen, Novartis and Roche.

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