近日，英国伦敦大学学院Julian D. Gillmore团队研究了耐西古兰Ziclumeran基因编辑在遗传性ATTR伴多发性神经病中的应用。这一研究成果于2025年9月25日发表在《新英格兰医学杂志》上。

遗传性甲状腺转蛋白淀粉样变性伴多神经病变（ATTRv-PN）是一种罕见的、多系统的、进行性的、衰弱的、致命的疾病，其特征是周围神经中错误折叠的甲状腺转蛋白（TTR）的组织沉积。Nexiguran ziclumeran （nex-z）是一种基于CRISPR-Cas9（聚集规律间隔的短回复性重复序列和相关的Cas9内切酶）的体内治疗药物，旨在通过选择性失活肝脏中的TTR来降低血清TTR水平。

在这项1期开放标签研究中，研究组给ATTRv-PN患者输注一次nex-z。主要目的包括评估nex-z的安全性和药效学。次要终点包括家族性淀粉样蛋白多发性神经病变分期的变化、多发性神经病变残疾评分、血清神经丝轻链（NfL）水平、修正体重指数（修正BMI，定义为常规BMI[体重以公斤为单位除以身高以米为单位的平方]乘以白蛋白以克/升为单位的水平）、修正神经病变损害评分+7 （mNIS+7；范围0 ~ 304，得分越高，损害越大）。

共36例患者接受nex-z治疗；平均随访27个月。与基线相比，血清TTR水平的平均变化百分比为第28天达到90%，持续到第24个月（92%）。与治疗相关的不良事件包括短暂的输注相关反应（21例），甲状腺素水平下降，但无甲状腺功能减退或促甲状腺素水平升高（8例），头痛（4例）。一名参与者死于心脏淀粉样变性，一名参与者因运动功能进行性下降而退出。11例患者报告了严重不良事件。24个月时，29例和27例患者的家族性淀粉样蛋白多神经病变分期和多神经病变失能评分保持稳定；2、5分别改善；在第2和第2期分别恶化。血清NfL水平的平均变化为9.0 pg /毫升，修正BMI的变化为24.7。与基线相比，mNIS+7的平均变化为8.5。

研究结果表明，在ATTRv-PN患者中，单次给药nex-z与血清TTR水平的快速、深度和持久降低有关。结果支持进一步研究nex-z治疗ATTRv-PN。

附：英文原文

Title: Nexiguran Ziclumeran Gene Editing in Hereditary ATTR with Polyneuropathy

Author: Julian D. Gillmore, Ed Gane, Jrg Tubel, Bjrn Pilebro, Andoni Echaniz-Laguna, Justin Kao, William Litchy, Safi Shahda, Alexandra Haagensen, Liron Walsh, Derek Smith, Jessica Kachadourian, Jonathan H. Ward, David Lebwohl, Peijuan Zhu, Yuanxin Xu, Adia Leung, Alison Sonderfan, David E. Gutstein, Garen Manvelian, David Adams

Issue&Volume: 2025-09-25

Abstract:

BACKGROUND

Hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN) is a rare, multisystem, progressive, debilitating, and fatal disease characterized by tissue deposition of misfolded transthyretin (TTR) in peripheral nerves. Nexiguran ziclumeran (nex-z) is an investigational in vivo therapy based on CRISPR-Cas9 (clustered regularly interspaced short palindromic repeats and associated Cas9 endonuclease) that is designed to reduce serum TTR levels through selective inactivation of TTR in the liver.

METHODS

In this phase 1, open-label study, we administered one infusion of nex-z to patients with ATTRv-PN. Primary objectives included assessment of the safety and pharmacodynamics of nex-z. Secondary end points included changes in the familial amyloid polyneuropathy stage, polyneuropathy disability score, serum neurofilament light chain (NfL) level, modified body-mass index (modified BMI, defined as the conventional BMI [weight in kilograms divided by square of height in meters] multiplied by the albumin level in grams per liter), and modified Neuropathy Impairment Score+7 (mNIS+7; range, 0 to 304, with higher scores indicating more impairment).

RESULTS

A total of 36 patients received nex-z; the mean follow-up was 27 months. The mean percent change from baseline in the serum TTR level was 90% at day 28, which was sustained through month 24 (92%). Treatment-related adverse events included transient infusion-related reactions (in 21 patients), decreased thyroxine level without hypothyroidism or elevated thyrotropin level (in 8), and headache (in 4). One participant died from cardiac amyloidosis, and one withdrew owing to progressive decline in motor function. Serious adverse events were reported in 11 patients. At month 24, the familial amyloid polyneuropathy stage and polyneuropathy disability score remained stable in 29 and 27 patients, respectively; improved in 2 and 5, respectively; and worsened in 2 and 2, respectively. The mean change in the serum NfL level was 9.0 pg per milliliter, and the change in the modified BMI was 24.7. The mean change from baseline in the mNIS+7 was 8.5.

CONCLUSIONS

A single administration of nex-z in patients with ATTRv-PN was associated with rapid, deep, and durable reductions in serum TTR levels. The results support further investigation of nex-z to treat ATTRv-PN.

DOI: NJ202509250000004

Source: https://www.nejm.org/doi/full/10.1056/NEJMoa2510209