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Cited by 30Retinal Development and DisordersVirus-based gene therapy researchRNA Interference and Gene Delivery

Genetic treatment for autosomal dominant inherited retinal dystrophies: Approaches, challenges and targeted genotypes

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Daich Varela, Malena, Georgiadis, Anastasios, Michaelides, Michel·2023·British Journal of Ophthalmology
DOI 10.1136/bjo-2022-321903
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Abstract

Inherited retinal diseases (IRDs) have been in the front line of gene therapy development for the last decade, providing a useful platform to test novel therapeutic approaches. More than 40 clinical trials have been completed or are ongoing, tackling autosomal recessive and X-linked conditions, mostly through adeno-associated viral vector delivery of a normal copy of the disease-causing gene. However, only recently has autosomal dominant (ad) disease been targeted, with the commencement of a trial for rhodopsin (RHO)-associated retinitis pigmentosa (RP), implementing antisense oligonucleotide (AON) therapy, with promising preliminary results (NCT04123626). Autosomal dominant RP represents 15%–25% of all RP, with RHO accounting for 20%–30% of these cases. Autosomal dominant macular and cone-rod dystrophies (MD/CORD) correspond to approximately 7.5% of all IRDs, and approximately 35% of all MD/CORD cases, with the main causative gene being BEST1. Autosomal dominant IRDs are not only less frequent than recessive, but also tend to be less severe and have later onset; for example, an individual with RHO-adRP would typically become severely visually impaired at an age 2–3 times older than in X-linked RPGR-RP. Gain-of-function and dominant negative aetiologies are frequently seen in the prevalent adRP genes RHO,RP1 and PRPF31 among others, which would not be effectively addressed by gene supplementation alone and need creative, novel approaches. Zinc fingers, RNA interference, AON, translational read-through therapy, and gene editing by clustered regularly interspaced short palindromic repeats/Cas are some of the strategies that are currently under investigation and will be discussed here.

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  • Most therapeutic strategies currently under investigation for inherited retinal dystrophies are gene- or mutation-specific, which limits their broad applicability.

    “Although several therapeutic strategies are currently under investigation, most are gene- or mutation-specific, which limits their broad applicability [5,6].”

    From Precise CRISPR/Cas9 and Cas12 Correction Using Lipoplexes in Retinal Models Derived from Patients with Inherited Retinal Dystrophies (2026) · cites this paper as [5]

    The Gene-independent approaches section says mutation-specific therapies may be time- or economically inefficient, and contrasts them with approaches that could apply to many genes. This supports the concern about limited applicability, but the paper focuses on autosomal dominant inherited retinal dystrophies and does not establish that most strategies under investigation across all inherited retinal dystrophies are gene- or mutation-specific. No page number is available in our copy. (LLM, conf=0.84)

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Cited by

Sorted by citations

Authors
Daich Varela, M., Georgiadis, A., & Michaelides, M.
Affiliations
Moorfields Eye Hospital (GB)
Corresponding author
Michaelides, Michel
ORCID
Venue
British Journal of Ophthalmology
Publisher
BMJ
Published
2022-08-29
Volume
107
Issue
9
Pages
1223-1230
ISSN
  • 0007-1161 (ISSN-L)
  • 1468-2079
DOI
10.1136/bjo-2022-321903
OpenAlex
W4293491746
Cited by
30
References
3
Citations by year
2026: 4 · 2025: 10 · 2024: 7 · 2023: 8 · 2022: 1
FWCI
0.68
Type
journal article
Language
en
Open access
Locations
  • British Journal of Ophthalmology (publishedVersion)
  • PubMed (publishedVersion)
  • UCL Discovery (University College London) (submittedVersion)
  • HighWire Press Open Archive (submittedVersion)
Funders
  • National Institute for Health Research
  • Moorfields Eye Charity
  • Wellcome Trust (099173/Z/12/Z)
  • Retina UK
  • Foundation Fighting Blindness
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
Keywords
gene therapy, retinitis pigmentosa, rhodopsin, BEST1, antisense therapy, adeno-associated virus vectors, gain-of-function mutations, dominant negative mutation, zinc finger nucleases, RNA interference, CRISPR/Cas9 genome editing, RP1, PRPF31
MeSH terms
Cone-Rod Dystrophies, Bestrophins, Child, Preschool, Eye Proteins, Genotype, Humans, Mutation, Retina, Retinitis Pigmentosa, Rhodopsin

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