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

Molecular Therapy: Nucleic Acids (Mar 2024)

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

Affiliations

Shun-Yun Cheng: Department of Ophthalmology and Visual Sciences, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA; Horae Gene Therapy Center, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA; Department of Neurobiology, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
Jillian Caiazzi: RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
Annabelle Biscans: RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
Julia F. Alterman: RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
Dimas Echeverria: RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
Nicholas McHugh: RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
Matthew Hassler: RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
Samson Jolly: Department of Ophthalmology and Visual Sciences, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
Delaney Giguere: Department of Ophthalmology and Visual Sciences, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
Joris Cipi: Department of Ophthalmology and Visual Sciences, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
Anastasia Khvorova: RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA; Corresponding author: Anastasia Khvorova, PhD, RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA.
Claudio Punzo: Department of Ophthalmology and Visual Sciences, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA; Horae Gene Therapy Center, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA; Department of Neurobiology, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA; Corresponding author: Claudio Punzo, PhD, Department of Ophthalmology and Visual Sciences, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA.

Journal volume & issue: Vol. 35, no. 1
p. 102088

Abstract

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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.

Published in Molecular Therapy: Nucleic Acids

ISSN: 2162-2531 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Therapeutics. Pharmacology
Website: https://www.cell.com/molecular-therapy-family/nucleic-acids/latest-content

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