"Pre-clinical development of siRNA Therapy for Autosomal Dominant Osteopetrosis (ADO)"

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 intargeting bone without exacerbating any inherent toxicity due to used vector. SiSaf’s sil-icon stabilized hybrid lipid nanoparticles (sshLNPs) constitute next-generation non-viral vectors able to retain the integrity and stability of constructs and to accommodate considerable pay-loads 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 demon-strating safety. The pre-clinical results will enable advanced pre-clinical development of RNA-based therapy for orphan and genetic skeletal disorders by safely and effectively delivering bio- logicals of interest to cure human systemic conditions.