PDF(Pubmed)
Abstract：
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.
摘要：
罕见的骨骼疾病仍然需要适当的临床上可用的转染剂，因为人类首创翻译的主要挑战涉及靶向骨骼而不加剧由于使用的载体而引起的任何固有毒性的内在困难。SiSaf的硅稳定的混合脂质纳米颗粒（sshLNP）构成了下一代非病毒载体，能够保持构建体的完整性和稳定性，并适应相当大的生物制品有效载荷，不需要冷链存储。将sshLNP与针对人CLCN7G215RmRNA特别设计的小干扰RNA(siRNA)复合。在青春期前常染色体显性骨症2型（ADO2）小鼠中通过单次腹膜内注射进行测试时，携带Clcn7基因（Clcn7G213R）的杂合突变，sshLNP,这在48小时时显著下调了股骨中Clcn7G213R相关的mRNA水平。在治疗后2周和4周观察到确认结果（3次腹膜内注射/周），挽救骨表型并证明安全性。临床前结果将通过安全有效地提供感兴趣的生物制剂来治愈人类全身性疾病，从而实现基于RNA的孤儿和遗传性骨骼疾病治疗的先进临床前开发。
