Effect of Allele-Specific Clcn7 G213R siRNA Delivered Via a Novel Nanocarrier on Bone Phenotypes in ADO2 Mice on 129S Background.

Autor: Saffie-Siebert S; SiSaf Ltd, Guildford, Surrey, GU2 7RE, UK. saffie@sisaf.com., Alam I; Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, 46202, USA. ialam@iu.edu., Sutera FM; SiSaf Ltd, Guildford, Surrey, GU2 7RE, UK., Dehsorkhi A; SiSaf Ltd, Guildford, Surrey, GU2 7RE, UK., Torabi-Pour N; SiSaf Ltd, Guildford, Surrey, GU2 7RE, UK., Baran-Rachwalska P; SiSaf Ltd, Guildford, Surrey, GU2 7RE, UK., Iamartino L; SiSaf Ltd, Guildford, Surrey, GU2 7RE, UK., Teti A; Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, 67100, L'Aquila, Italy., Maurizi A; Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, 67100, L'Aquila, Italy., Gerard-O'Riley RL; Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, 46202, USA., Acton D; Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, 46202, USA., Econs MJ; Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.; Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.
Jazyk: angličtina
Zdroj: Calcified tissue international [Calcif Tissue Int] 2024 Jul; Vol. 115 (1), pp. 85-96. Date of Electronic Publication: 2024 May 11.
DOI: 10.1007/s00223-024-01222-3
Abstrakt: Autosomal dominant osteopetrosis type 2 (ADO2) is a rare inherited bone disorder characterised by dense but brittle bones. It displays striking phenotypic variability, with the most severe symptoms, including blindness and bone marrow failure. Disease management largely relies on symptomatic treatment since there is no safe and effective treatment. Most ADO2 cases are caused by heterozygous loss-of-function mutations in the CLCN7 gene, which encodes an essential Cl - /H + antiporter for proper bone resorption by osteoclasts. Thus, siRNA-mediated silencing of the mutant allele is a promising therapeutic approach, but targeting bone for first-in-human translation remains challenging. Here, we demonstrate the utility of silicon-stabilised hybrid lipid nanoparticles (sshLNPs) as a next-generation nucleic acid nanocarrier capable of delivering allele-specific siRNA to bone. Using a Clcn7 G213R knock-in mouse model recapitulating one of the most common human ADO2 mutations and based on the 129S genetic background (which produces the most severe disease phenotype amongst current models), we show substantial knockdown of the mutant allele in femur when siRNA targeting the pathogenic variant is delivered by sshLNPs. We observed lower areal bone mineral density in femur and reduced trabecular thickness in femur and tibia, when siRNA-loaded sshLNPs were administered subcutaneously (representing the most relevant administration route for clinical adoption and patient adherence). Importantly, sshLNPs have improved stability over conventional LNPs and enable 'post hoc loading' for point-of-care formulation. The treatment was well tolerated, suggesting that sshLNP-enabled gene therapy might allow successful clinical translation of essential new treatments for ADO2 and potentially other rare genetic bone diseases.
(© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
Databáze: MEDLINE
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