Clinical challenges: gene replacement therapy for hereditary retinal diseases

Inherited retinal diseases (IRDs) – a group of genetically altered disorders that lead to serious visual impairment or blindness – have long been considered incurable.

Research developments over the past twenty years have allowed To determine More than 260 gene mutations associated with IRDs, and multiple studies Gene Replacement Therapies He hopes to slow the progression of the disease and possibly restore some degree of visual function is in progress.

“Types of therapies being explored include single-gene gene therapies, which target and replace or correct the mutated gene; for example, our first and only FDA-approved drug, voretigene neparvovec-rzyl, encodes for RPE65, a protein used by patients with biallelic patients. RPE65 The mutations are missing,” said Christina Wing, MD, MBA, of Baylor College of Medicine and Collin Eye Institute in Houston, MedPage today. “Other therapies appear to affect the visual modulation cycle that is disrupted in these diseases. Stem cells and regenerative therapies are being explored, although they have not been very successful so far.”

While gene therapy is not a cure for IRDs, it does provide a way to control disease progression by treating the defective gene that causes the disease. This means that it is given as a one-time treatment without the need for repeated interventions, unlike some treatments for retinal diseases that require direct injections once every 3 months. Currently, clinical trials in IRDs focus on approaches based on adeno-associated virus (AAV) that require subretinal injection.

in last reviewThe researchers describe “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
  • Targeting mRNA with antisense oligonucleotides (ASOs) for gene knockdown and splicing modification.
  • Optogenetic approaches that “aims to replace the function of native retinal photoreceptors by engineering other types of retinal cells 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 disease (ABCA4)
  • Achromatopsia (CNGA3And the CNGB3)
  • Usher syndrome (MYO7A)
  • chorion (CHM)
  • congenital Leber’s diseaseCEP290)
  • X-linked retinitis pigmentosa (RPGR)
  • X-linked retinal cleavage (RS1)
  • Leber’s hereditary optic neuropathyND4)

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

“One candidate drug for dry macular degeneration, avacincaptad pegol (complementary factor C5 inhibitor) is being studied in the Iveric Bio STAR study of patients with autosomal recessive Stargardt disease 1 (STGD1),” Weng noted. “The phase II study, TEASE, sponsored by Alkeus, explores 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 studying a subretinal gene therapy called AGTC-501 for patients with X-linked retinitis pigmentosa with the RPGR Boom, Wong added. “Interim results It was announced in May 2021 that at 12 months, 50% of high-dose patients showed a positive response to treatment based on visual sensitivity, with some even seeing an improvement in visual acuity.”

in Discussion 2021the researchers note that innovative approaches are used for genes that are too large to match the AAV delivery vector used with RPE65 gene, adding that ASOs are being investigated in clinical trials for patients with Usher syndrome and retinitis pigmentosa.

Optogenetics is also interesting, Wing said, “because his agnostic approach to genetics would allow for application to multiple genetic retinal diseases rather than just a small number with a specific mutation.” “In this form of treatment, gene therapy essentially converts some cells of the retina into light-sensitive cells with a photoreceptor-like function.”

Nanoscope has recently finished registration for Phase IIb Gene therapy trial She added that it is for the treatment of retinitis pigmentosa. The previous phase I/IIa trial included 11 patients [with retinitis pigmentosa] It showed that MCO-010 was well tolerated and improved functional vision in patients with advanced disease. Additionally, this treatment is given as a single intravitreal injection that can be given in the clinic.”

Results from the Phase 2B study are expected in 2023, and the same treatment is being evaluated in a Phase 2 trial for Stargardt disease, Wing said.

The malignant nature of IRDs means that the structural changes they cause may be very subtle early in the course of the disease, and will become easier to quantify over the years as the disease progresses, making functional evaluation of the clinical outcomes of IRD treatments difficult.

  • author['full_name']

    Kate Knissl Freelance medical journalist based in Belleville, Ontario.


Wong has reported on his relationships with Alcon, Almera Sciences, Allergan/AbbVie, the Dutch Eye Research Center, Genentech, Novartis, Regeneron and Regenxbio.

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