英国伦敦大学学院Julian D. Gillmore团队研究了CRISPR-Cas9体内基因编辑治疗转甲状腺素淀粉样变的效果。相关论文发表在2021年6月26日出版的《新英格兰医学杂志》上。

转甲状腺素淀粉样变，又称ATTR淀粉样变，是一种危及生命的疾病，其特征是错误折叠的转甲状腺素（TTR）蛋白在组织（主要是神经和心脏）中进行性积累。NTLA-2001是一种体内基因编辑治疗剂，旨在通过降低血清中TTR的浓度来治疗ATTR淀粉样变。它基于规律间隔成簇短回文重复序列和相关的Cas9内切酶（CRISPR-Cas9）系统，包括一个封装Cas9蛋白信使RNA的脂质纳米颗粒和一个靶向TTR的单导向RNA。

在进行临床前体外和体内研究后，研究组进行了一项1期临床试验，招募了6例遗传性ATTR淀粉样变伴多发性神经病变患者，对单次递增NTLA-2001给药的安全性和药效作用进行评估，两个初始剂量组各3例（分别为0.1和0.3 mg/kg）。

临床前研究显示单次给药后TTR持久敲除。在患者输注后28天进行的一系列安全性评估显示，几乎没有不良事件发生，而那些确实发生的不良事件级别均很轻微。研究组观察到剂量依赖性药效作用。第28天，0.1 mg/kg剂量组的血清TTR蛋白浓度较基线平均降低了52%，而0.3 mg/kg剂量组的血清TTR蛋白浓度则降低了87%。

研究结果表明，对于一小部分遗传性ATTR淀粉样变合并多发性神经病变的患者，使用NTLA-2001只与轻微不良事件相关，并通过靶向敲除TTR导致血清TTR蛋白浓度显著降低。

附：英文原文

Title: CRISPR-Cas9 In Vivo Gene Editing for Transthyretin Amyloidosis | NEJM

Author: Julian D. Gillmore, M.D., Ph.D.,, Ed Gane, M.B., Ch.B.,, Jorg Taubel, M.D.,, Justin Kao, M.B., Ch.B.,, Marianna Fontana, M.D., Ph.D.,, Michael L. Maitland, M.D., Ph.D.,, Jessica Seitzer, B.S.,, Daniel O’Connell, Ph.D.,, Kathryn R. Walsh, Ph.D.,, Kristy Wood, Ph.D.,, Jonathan Phillips, Ph.D.,, Yuanxin Xu, M.D., Ph.D.,, Adam Amaral, B.A.,, Adam P. Boyd, Ph.D.,, Jeffrey E. Cehelsky, M.B.A.,, Mark D. McKee, M.D.,, Andrew Schiermeier, Ph.D.,, Olivier Harari, M.B., B.Chir., Ph.D.,, Andrew Murphy, Ph.D.,, Christos A. Kyratsous, Ph.D.,, Brian Zambrowicz, Ph.D.,, Randy Soltys, Ph.D.,, David E. Gutstein, M.D.,, John Leonard, M.D.,, Laura Sepp-Lorenzino, Ph.D.,, and David Lebwohl, M.D.

Issue&Volume: 2021-06-26

Abstract:

Background

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.

Methods

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.

Results

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.

Conclusions

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.

DOI: 10.1056/NEJMoa2107454

Source: https://www.nejm.org/doi/full/10.1056/NEJMoa2107454