Single intravitreal administration of a tetravalent siRNA exhibits robust and efficient gene silencing in mouse and pig photoreceptors

Inherited retinal dystrophies caused by dominant mutations in photoreceptor (PR) cell expressed genes are a major cause of irreversible vision loss. Oligonucleotide therapy has been of interest in diseases that conventional medicine cannot target. In the early days, small interfering RNAs (siRNAs) w...

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Bibliographic Details
Published in:	Molecular therapy. Nucleic acids Vol. 35; no. 1; p. 102088
Main Authors:	Cheng, Shun-Yun, Caiazzi, Jillian, Biscans, Annabelle, Alterman, Julia F., Echeverria, Dimas, McHugh, Nicholas, Hassler, Matthew, Jolly, Samson, Giguere, Delaney, Cipi, Joris, Khvorova, Anastasia, Punzo, Claudio
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 12-03-2024 American Society of Gene & Cell Therapy Elsevier
Subjects:	gene silencing inherited retinal dystrophy IRD MT: Oligonucleotides: Therapies and Applications multivalency Original photoreceptors siRNA photoreceptors MT: Oligonucleotides: Therapies and Applications inherited retinal dystrophy gene silencing siRNA IRD multivalency
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Summary:	Inherited retinal dystrophies caused by dominant mutations in photoreceptor (PR) cell expressed genes are a major cause of irreversible vision loss. Oligonucleotide therapy has been of interest in diseases that conventional medicine cannot target. In the early days, small interfering RNAs (siRNAs) were explored in clinical trials for retinal disorders with limited success due to a lack of stability and efficient cellular delivery. Thus, an unmet need exists to identify siRNA chemistry that targets PR cell expressed genes. Here, we evaluated 12 different fully chemically modified siRNA configurations, where the valency and conjugate structure were systematically altered. The impact on retinal distribution following intravitreal delivery was examined. We found that the increase in valency (tetravalent siRNA) supports the best PR accumulation. A single intravitreal administration induces multimonths efficacy in rodent and porcine retinas while demonstrating a good safety profile. The data suggest that this configuration can treat retinal diseases caused by PR cell expressed genes with 1–2 intravitreal injections per year. [Display omitted] Punzo and colleagues have identified in a screen a chemically modified tetrameric siRNA that exhibits efficient long-term gene silencing in photoreceptor cells of mouse and swine eyes. This tetrameric siRNA chemistry may be used for the treatment of retinal diseases caused by mutations in photoreceptor cell expressed genes.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2162-2531 2162-2531
DOI:	10.1016/j.omtn.2023.102088