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CRISPR-Cas9 In Vivo Gene Editing for Transthyretin Amyloidosis

转甲状腺素 医学 淀粉样变性 体内 多发性神经病 药效学 药理学 淀粉样变性 病理 内科学 药代动力学 免疫学 生物 遗传学 免疫球蛋白轻链 抗体
作者
Julian D. Gillmore,Ed Gane,Jörg Täubel,Justin Kao,Marianna Fontana,Michael L. Maitland,Jessica Seitzer,Daniel J. O’Connell,Ken Walsh,Kristy M. Wood,J. A. Phillips,Yuanxin Xu,Adam Amaral,Adam P. Boyd,Jeffrey Cehelsky,Mark D. McKee,Andrew Schiermeier,Olivier Harari,Andrew Murphy,Christos A. Kyratsous,Brian Zambrowicz,Randy Soltys,David E. Gutstein,John P. Leonard,Laura Sepp‐Lorenzino,David Lebwohl
出处
期刊:The New England Journal of Medicine [New England Journal of Medicine]
卷期号:385 (6): 493-502 被引量:859
标识
DOI:10.1056/nejmoa2107454
摘要

Transthyretin amyloidosis, also called ATTR amyloidosis, is a life-threatening disease characterized by progressive accumulation of misfolded transthyretin (TTR) protein in tissues, predominantly the nerves and heart. NTLA-2001 is an in vivo gene-editing therapeutic agent that is designed to treat ATTR amyloidosis by reducing the concentration of TTR in serum. It is based on the clustered regularly interspaced short palindromic repeats and associated Cas9 endonuclease (CRISPR-Cas9) system and comprises a lipid nanoparticle encapsulating messenger RNA for Cas9 protein and a single guide RNA targeting TTR.After conducting preclinical in vitro and in vivo studies, we evaluated the safety and pharmacodynamic effects of single escalating doses of NTLA-2001 in six patients with hereditary ATTR amyloidosis with polyneuropathy, three in each of the two initial dose groups (0.1 mg per kilogram and 0.3 mg per kilogram), within an ongoing phase 1 clinical study.Preclinical studies showed durable knockout of TTR after a single dose. Serial assessments of safety during the first 28 days after infusion in patients revealed few adverse events, and those that did occur were mild in grade. Dose-dependent pharmacodynamic effects were observed. At day 28, the mean reduction from baseline in serum TTR protein concentration was 52% (range, 47 to 56) in the group that received a dose of 0.1 mg per kilogram and was 87% (range, 80 to 96) in the group that received a dose of 0.3 mg per kilogram.In a small group of patients with hereditary ATTR amyloidosis with polyneuropathy, administration of NTLA-2001 was associated with only mild adverse events and led to decreases in serum TTR protein concentrations through targeted knockout of TTR. (Funded by Intellia Therapeutics and Regeneron Pharmaceuticals; ClinicalTrials.gov number, NCT04601051.).
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