非典型溶血尿毒综合征
补体成分5
阵发性夜间血红蛋白尿
药理学
生物
抗体
RNA干扰
基因沉默
免疫学
癌症研究
小干扰RNA
补体系统
化学
转染
生物化学
基因
核糖核酸
作者
Anna Borodovsky,Kristina Yucius,Andrew Sprague,Nirmal K. Banda,V. Michael Holers,Akshay Vaishnaw,Martin A. Maier,Rajeev Kallanthottathil,Klaus Charissé,Satya Kuchimanchi,Muthiah Manoharan,David J. Salant,Kevin Fitzgerald,Rachel Meyers,Benny Sørensen
出处
期刊:Blood
[American Society of Hematology]
日期:2014-12-06
卷期号:124 (21): 1606-1606
被引量:12
标识
DOI:10.1182/blood.v124.21.1606.1606
摘要
Abstract Excessive complement activation plays a pivotal role in a variety of disorders. Complement component C5 is a clinically validated therapeutic target for treatment of both paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic-uremic syndrome. We developed a robust RNAi therapeutics platform for the delivery of siRNAs to the liver using trivalent GalNAc conjugates, enabling specific silencing of hepatocyte-expressed genes following subcutaneous (SC) injection. The liver produces essentially the entirety of C5 and other complement pathway proteins. We are developing ALN-CC5, an investigational RNAi therapeutic targeting human, primate and rodent C5. C5 silencing and complement activity inhibition were examined in rodents and primates. Multi-dose SC ALN-CC5 treatment resulted in sustained lowering of cyno serum C5 with ≤3% residual protein remaining. C5 reduction was associated with >90% and >95% inhibition of classical and alternative complement pathways as measured by ELISA-based assays. Additionally, >80% lowering of complement serum hemolytic activity was observed. ALN-CC5 was safe and well tolerated in both rat and non-human primate toxicology studies. In addition to wild type animals, ALN-CC5 was tested in several animal models of disease in which complement activation plays a prominent role. Silencing of murine C5 was highly efficacious in a model of anti-collagen antibody-induced arthritis with a disease modifying activity equivalent to that of an anti-C5 antibody. Furthermore, C5 silencing was effective at reducing proteinuria in a rat model of membranous nephropathy. Up-regulation of C5 expression, observed in both models, had no effect on the extent of C5 silencing, suggesting that ALN-CC5 could be efficacious in the context of inflammation. These data demonstrate a prominent role for circulating, liver-derived C5 in mediating pathology at extrahepatic sites and the potential utility of an RNAi therapeutic targeting C5. In summary, RNAi-mediated silencing of liver-derived C5 is a promising novel therapeutic approach for inhibiting systemic complement activity, with the potential to enable, low volume, subcutaneous treatment for patients with PNH and other disorders where complement activation plays a role in disease progression. Disclosures Borodovsky: Alnylam: Employment. Yucius:Alnylam: Employment. Sprague:Alnylam: Employment. Banda:Alnylam: Research Funding. Holers:Alnylam: Research Funding. Vaishnaw:Alnylam Pharmaceuticals: Employment, Equity Ownership. Maier:Alnylam: Employment. Kallanthottathil:Alnylam: Employment. Charisse:Alnylam: Employment. Kuchimanchi:Alnylam: Employment. Manoharan:Alnylam: Employment. Salant:Alnylam: Honoraria. Fitzgerald:Alnylam: Employment. Meyers:Alnylam: Employment. Sorensen:Alnylam Pharmaceuticals: Employment, Equity Ownership.
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