Novel hybrid silicon-lipid nanoparticles deliver a siRNA to cure autosomal dominant osteopetrosis in mice. Implications for gene therapy in humans.
| Autor: | Maurizi A; Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy., Patrizii P; Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy., Teti A; Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy., Sutera FM; SiSaf Limited, Guildford, UK., Baran-Rachwalska P; SiSaf Limited, Guildford, UK., Burns C; PorousSilicon, Salzburg, Austria., Nandi U; SiSaf Limited, Guildford, UK., Welsh M; SiSaf Limited, Guildford, UK., Torabi-Pour N; SiSaf Limited, Guildford, UK., Dehsorkhi A; SiSaf Limited, Guildford, UK., Saffie-Siebert S; SiSaf Limited, Guildford, UK. |
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| Jazyk: | angličtina |
| Zdroj: | Molecular therapy. Nucleic acids [Mol Ther Nucleic Acids] 2023 Aug 19; Vol. 33, pp. 925-937. Date of Electronic Publication: 2023 Aug 19 (Print Publication: 2023). |
| DOI: | 10.1016/j.omtn.2023.08.020 |
| Abstrakt: | Rare skeletal diseases are still in need of proper clinically available transfection agents as the major challenge for first-in-human translation relates to intrinsic difficulty in targeting bone without exacerbating any inherent toxicity due to used vector. SiSaf's silicon stabilized hybrid lipid nanoparticles (sshLNPs) constitute next-generation non-viral vectors able to retain the integrity and stability of constructs and to accommodate considerable payloads of biologicals, without requiring cold-chain storage. sshLNP was complexed with a small interfering RNA (siRNA) specifically designed against the human CLCN7 G215R mRNA. When tested via single intraperitoneal injection in pre-puberal autosomal dominant osteopetrosis type 2 (ADO2) mice, carrying a heterozygous mutation of the Clcn7 gene ( Clcn7 G213R ), sshLNP, this significantly downregulated the Clcn7 G213R related mRNA levels in femurs at 48 h. Confirmatory results were observed at 2 weeks and 4 weeks after treatments (3 intraperitoneal injections/week), with rescue of the bone phenotype and demonstrating safety. The pre-clinical results will enable advanced preclinical development of RNA-based therapy for orphan and genetic skeletal disorders by safely and effectively delivering biologicals of interest to cure human systemic conditions. Competing Interests: A.T. and A.M. served as consultant, P.P had a service agreement, and F.M.S., N.T.-P., P.B.R, C.B., U.N., M.W., and A.D. are scientists working for SiSaf Ltd, a commercial stage biopharmaceutical company. S.S.-S. is founder and CEO of SiSaf Ltd. (© 2023 The Author(s).) |
| Databáze: | MEDLINE |
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