The Extraordinary Phenotypic and Genetic Variability of Retinal and Macular Degenerations: The Relevance to Therapeutic Developments.

Marco Nassisi, José-Alain Sahel, Christina Zeitz, Isabelle Audo

Journal: Cold Spring Harbor perspectives in medicine 2024;14(6):

PMID: 37604589

Abstract

Inherited retinal diseases (IRDs) are a clinically and genetically heterogeneous group of rare conditions leading to various degrees of visual handicap and to progressive blindness in more severe cases. Besides visual rehabilitation, educational, and socio-professional support, there are currently limited therapeutic options, but the approval of the first gene therapy product for -related IRDs raised hope for therapeutic innovations. Such developments are facing obstacles intrinsic to the disease and the affected tissue including the extreme phenotypic and genetic variability of IRDs and the fine tuning of visual processing through the complex architecture of the postmitotic neural retina. A precise phenotypic characterization is required prior to genetic testing, which now relies on high-throughput sequencing. Their challenges will be discussed within this article as well as their implications in clinical trial design.

Address: Sorbonne Université, INSERM, CNRS, Institut de la Vision, Paris 75012, France [email protected].; Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts, National Rare Disease Center REFERET and INSERM-DGOS CIC 1423, Paris F-75012, France.; Sorbonne Université, INSERM, CNRS, Institut de la Vision, Paris 75012, France.; Department of Clinical Sciences and Community Health, University of Milan, Milan 20122, Italy.; Ophthalmology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, Milan 20122, Italy.; Sorbonne Université, INSERM, CNRS, Institut de la Vision, Paris 75012, France.; Sorbonne Université, INSERM, CNRS, Institut de la Vision, Paris 75012, France.; Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts, National Rare Disease Center REFERET and INSERM-DGOS CIC 1423, Paris F-75012, France.; Department of Ophthalmology, University of Pittsburgh Medical School, Pittsburgh, Pennsylvania 15213, USA.

DOI: 10.1101/cshperspect.a041652

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MeSH Terms: Humans, Phenotype, Genetic Therapy, Macular Degeneration, Genetic Variation, cis-trans-Isomerases, Retinal Degeneration