Novel hybrid silicon-lipid nanoparticles deliver a siRNA to cure autosomal dominant osteopetrosis in mice. Implications for gene therapy in humans

• Main Authors: Antonio Maurizi (Author), Piergiorgio Patrizii (Author), Anna Teti (Author), Flavia Maria Sutera (Author), Paulina Baran-Rachwalska (Author), Chris Burns (Author), Uttom Nandi (Author), Michael Welsh (Author), Nissim Torabi-Pour (Author), Ashkan Dehsorkhi (Author), Suzanne Saffie-Siebert (Author)
• Format: Book
• Published: Elsevier, 2023-09-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.

Summary

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 CLCN7G215R 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 (Clcn7G213R), sshLNP, this significantly downregulated the Clcn7G213R 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.

Item Description

2162-2531
10.1016/j.omtn.2023.08.020