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

Shun-Yun Cheng; Jillian Caiazzi; Annabelle Biscans; Julia F Alterman; Dimas Echeverria; Nicholas McHugh; Matthew Hassler; Samson Jolly; Delaney Giguere; Joris Cipi; Anastasia Khvorova; Claudio Punzo

doi:10.1016/j.omtn.2023.102088

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

Mol Ther Nucleic Acids. 2023 Dec 5;35(1):102088. doi: 10.1016/j.omtn.2023.102088. eCollection 2024 Mar 12.

Authors

Shun-Yun Cheng^{1

2

3}, Jillian Caiazzi⁴, Annabelle Biscans⁴, Julia F Alterman⁴, Dimas Echeverria⁴, Nicholas McHugh⁴, Matthew Hassler⁴, Samson Jolly¹, Delaney Giguere¹, Joris Cipi¹, Anastasia Khvorova⁴, Claudio Punzo^{1

2

3}

Affiliations

¹ Department of Ophthalmology and Visual Sciences, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA.
² Horae Gene Therapy Center, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA.
³ Department of Neurobiology, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA.
⁴ RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA.

Abstract

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.

Keywords: IRD; MT: Oligonucleotides: Therapies and Applications; gene silencing; inherited retinal dystrophy; multivalency; photoreceptors; siRNA.

Abstract

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