Genetic treatment of autosomal dominant hereditary retinal dystrophies: approaches, issues and targeted genotypes



Inherited retinal diseases (IRDs) have been at the forefront of gene therapy development over the past decade, providing a useful platform for testing new therapeutic approaches. Over 40 clinical trials have been completed or are ongoing, addressing autosomal recessive and X-linked diseases, primarily through the delivery of an adeno-associated viral vector of a normal copy of the disease-causing gene . However, autosomal dominant (ad) disease has only recently been targeted, with the start of a rhodopsin trial (ORH)-associated retinitis pigmentosa (RP), implementing antisense oligonucleotide (AON) therapy, with promising preliminary results (NCT04123626).

Autosomal dominant RP accounts for 15-25% of all RP, with ORH representing 20 to 30% of these cases. Autosomal dominant macular and conical dystrophies (MD/CORD) account for approximately 7.5% of all IRDs and approximately 35% of all MD/CORD cases, with the major causative gene being BEST1. Autosomal dominant IRDs are not only less common than recessive ones, but also tend to be less severe and appear later; for example, a person with ORH-adRP would typically become severely visually impaired at an age 2-3 times older than in X-linked cases RPGR-RP.

Gain of function and dominant negative etiologies are frequently seen in prevalent adRP genes ORH, RP1 and PRPF31 among others, which would not be treated effectively by gene supplementation alone and which require creative and innovative approaches. Zinc fingers, RNA interference, AON, translational read therapy and gene editing by regularly spaced clustered short palindromic repeats/Cases are some of the strategies that are currently being investigated and will be discussed here.

  • Retina
  • Genetic
  • Other treatment
  • Degeneration

Declaration of data availability

All data relevant to the study are included in the article or uploaded as additional information online.


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