NEJM：CRISPR-Cas9体内基因编辑方法治疗转甲状腺素蛋白淀粉样变性

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CRISPR-Cas9体内基因编辑方法治疗转甲状腺素蛋白淀粉样变性

CRISPR-Cas9 In Vivo Gene Editing for Transthyretin Amyloidosis

2021年8月5日

朗读者：Dr. Stephen Morrissey, NEJM常务执行主编

转甲状腺素蛋白淀粉样变性（ATTR淀粉样变性）是一种危及生命的疾病，其特征是错误折叠的TTR蛋白在组织中累积，其中主要是神经和心脏。NTLA-2001是一种体内基因编辑治疗剂，旨在通过降低血清TTR浓度的方式治疗ATTR淀粉样变性。短视频中总结了新的研究发现。

CRISPR-Cas9体内基因编辑方法治疗转甲状腺素蛋白淀粉样变性

CRISPR-Cas9 In Vivo Gene Editing for Transthyretin Amyloidosis

摘 要

背景

转甲状腺素蛋白淀粉样变性（又称ATTR淀粉样变性）是一种危及生命的疾病，其特征是错误折叠的转甲状腺素蛋白（TTR）在组织（主要是神经和心脏）内进行性累积。NTLA-2001是一种体内基因编辑治疗剂，旨在通过降低血清TTR浓度的方式治疗ATTR淀粉样变性。它是基于规律成簇的间隔短回文重复序列和相关Cas9核酸内切酶（CRISPR-Cas9）系统，由含有Cas9蛋白信使RNA和靶向TTR的单向导RNA的脂质纳米颗粒组成。

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.

方法

进行临床前体外和体内研究之后，在一项进行中的1期临床研究中，我们在6例遗传性ATTR淀粉样变性合并多发性神经病患者中评估了递增剂量NTLA-2001单次给药的安全性和药效学作用，两个初始剂量组（0.1 mg/kg和0.3 mg/kg）各3例患者。

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.

结果

临床前研究表明，单次给药可持久敲除TTR。我们在患者输入NTLA-2001后28天内进行的系列安全性评估显示，不良事件很少，而且为轻度。我们观察到剂量依赖性药效学作用。第28日时，0.1 mg/kg剂量组的血清TTR蛋白浓度相对于基线的平均降幅为52%（范围，47~56），0.3 mg/kg剂量组的降幅为87%（范围，80~96）。

Result

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.

结论

NTLA-2001用于少数几例遗传性ATTR淀粉样变性合并多发性神经病患者之后仅发生了轻度不良事件，并且通过靶向敲除TTR的方式降低了血清TTR蛋白浓度。（由Intellia Therapeutics和再生元制药[Regeneron Pharmaceuticals]资助；在ClinicalTrials.gov注册号为NCT04601051。）

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. (Funded by Intellia Therapeutics and Regeneron Pharmaceuticals; ClinicalTrials.gov number, NCT04601051.)

Julian D. Gillmore, Ed Gane, Jorg Taubel, et al. CRISPR-Cas9 In Vivo Gene Editing for Transthyretin Amyloidosis. DOI: 10.1056/NEJMoa2107454