[Pubmed] Identification of potent siRNA targeting complement C5 and its robust activity in pre-clinical models of myasth

[RSS-Bot]

Mol Ther Nucleic Acids. 2023 Jan 13;31:339-351. doi: 10.1016/j.omtn.2023.01.005. eCollection 2023 Mar 14.

ABSTRACT

Complement component 5 (C5), an important molecule in the complement cascade, blockade by antibodies shows clinical efficacy in treating complement-mediated disorders. However, insufficient blockading induced by single-nucleotide polymorphisms in the C5 protein or frequent development of "breakthrough" intravascular hemolysis in patients with paroxysmal nocturnal hemoglobinuria treated with eculizumab have been reported. Herein, we developed a lipid nanoparticle (LNP)-formulated siRNA targeting C5 that was efficiently delivered to the liver and silenced C5 expression. We identified a potent C5-siRNA with an in vitro IC50 of 420 pM and in vivo ED50 of 0.017 mg/kg following a single administration. Single or repeated administrations of the LNP-formulated C5-siRNA allowed robust and durable suppression of liver C5 expression in mice. Complement C5 silencing ameliorated C5b-dependent anti-acetylcholine receptor antibody-induced myasthenia gravis and C5a-dependent collagen-induced arthritis symptoms. Similarly, in nonhuman primates, a single administration of C5-siRNA/LNP-induced dose-dependent plasma C5 suppression and concomitantly inhibited serum complement activity; complement activity recovered to the pre-treatment levels at 65 days post administration, thus indicating that the complement activity can be controlled for a specific period. Our findings provide the foundation for further developing C5-siRNA delivered via LNPs as a potential therapeutic for complement-mediated diseases.

PMID:36789273 | PMC:PMC9900455 | DOI:10.1016/j.omtn.2023.01.005


Source: https://pubmed.ncbi.nlm.nih.gov/3678927 ... t6+86293ac