Snorradottir Asbjorg Osk, Gutierrez-Uzquiza Alvaro, Bragado Paloma, March Michael E, Kao Charlly, Arkink Enrico Bernardo, Jonsdottir Solveig, Sigurdardottir Arna, Isaksson Helgi J, Mariasdóttir Hekla Liv, Bjorgvinsdottir Olga Yr, Kowal Natalia M, Heimisdottir Hugrun L, Sverrisdottir Astros, Palsdottir Astridur, Bjornsson Hans Tomas, Hakonarson Hakon
Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
Department of Pathology, Landspitali University Hospital, Reykjavik, Iceland.
JAMA Neurol. 2025 May 1;82(5):486-494. doi: 10.1001/jamaneurol.2025.0326.
Hereditary cystatin C amyloid angiopathy (HCCAA) is a lethal, dominantly inherited disease primarily affecting Icelandic young adults that leads to severe cerebral amyloid angiopathy, with no effective therapy.
To investigate safety, tolerance, and therapeutic potential of N-acetylcysteine (NAC) in lowering disease-associated biomarkers in sequence variation carriers.
DESIGN, SETTING, AND PARTICIPANTS: This phase 2a open-label clinical trial was conducted from March 2019 to December 2021 at a single study center at Landspitali University Hospital in Reykjavik, Iceland, and included 17 confirmed carriers of the L68Q-CST3 sequence variation.
High-dose NAC treatment was administered at 2400 mg daily for 9 months. Participants underwent regular monitoring for hemorrhages and disease progression, including blood and skin biopsy samples obtained every 3 months for biomarker testing.
The primary outcomes were drug tolerability and safety, cognitive status, and reduction in disease-associated biomarkers in skin biopsies. Secondary outcomes included changes in blood and plasma biomarker levels.
Of 17 carriers treated, 6 were male and 11 were female, and mean (SD) participant age was 40.0 (4.2) years. Analysis of the primary outcomes showed that NAC was safe and well tolerated. Five cerebral bleeds occurred during the treatment period without permanent neurological sequela; no death occurred. There was significant reduction in median (IQR) disease-specific biomarker levels in skin after treatment, including collagen IV (baseline: 3.69% [2.48%-5.16%]; after treatment: 2.60% [1.99%-2.97%]; P < .001), fibronectin (baseline: 3.17% [2.09%-5.05%]; after treatment: 2.37% [1.87%-3.42%]; P = .01), vimentin (baseline: 1.60% [1.24%-2.37%]; after treatment: 1.31% [0.97%-1.68%]; P < .001), and SMAD (baseline: 2.25% [0.55%-4.36%]; after treatment: 1.56% [0.20%-2.54%]; P < .001) via Wilcoxon matched-pairs signed rank test. Secondary outcomes included a significant increase in reduced glutathione levels and decreased high-molecular-weight cystatin C aggregate levels in plasma after NAC treatment.
In this single-center nonrandomized clinical trial, NAC was safe and well tolerated and decreased disease-associated biomarker and amyloid deposition, suggesting NAC may offer a preventive strategy against HCCAA.
ClinicalTrialsRegister.eu Identifier: 2017-004776-56.
遗传性胱抑素C淀粉样血管病（HCCAA）是一种致命的常染色体显性遗传病，主要影响冰岛年轻人，会导致严重的脑淀粉样血管病，且尚无有效治疗方法。
研究N-乙酰半胱氨酸（NAC）降低序列变异携带者中疾病相关生物标志物的安全性、耐受性及治疗潜力。
设计、地点和参与者：这项2a期开放标签临床试验于2019年3月至2021年12月在冰岛雷克雅未克Landspitali大学医院的一个研究中心进行，纳入了17名确诊的L68Q-CST3序列变异携带者。
给予高剂量NAC治疗，每日2400毫克，持续9个月。参与者接受定期的出血和疾病进展监测，包括每3个月采集血液和皮肤活检样本进行生物标志物检测。
主要结局为药物耐受性和安全性、认知状态以及皮肤活检中疾病相关生物标志物的降低。次要结局包括血液和血浆生物标志物水平的变化。
在接受治疗的17名携带者中，6名男性，11名女性，参与者平均（标准差）年龄为40.0（4.2）岁。对主要结局的分析表明，NAC安全且耐受性良好。治疗期间发生了5次脑内出血，无永久性神经后遗症；无死亡病例。治疗后皮肤中疾病特异性生物标志物水平的中位数（四分位间距）显著降低，包括IV型胶原（基线：3.69%[2.48%-5.16%]；治疗后：2.60%[1.99%-2.97%]；P＜0.001）、纤连蛋白（基线：3.17%[2.09%-5.05%]；治疗后：2.37%[1.87%-3.42%]；P = 0.01）、波形蛋白（基线：1.60%[1.24%-2.37%]；治疗后：1.31%[0.97%-1.68%]；P＜0.001）和SMAD（基线：2.25%[0.55%-4.36%]；治疗后：1.56%[0.20%-2.54%]；P＜0.001），采用Wilcoxon配对符号秩检验。次要结局包括NAC治疗后血浆中还原型谷胱甘肽水平显著升高和高分子量胱抑素C聚集体水平降低。
在这项单中心非随机临床试验中，NAC安全且耐受性良好，并降低了疾病相关生物标志物和淀粉样蛋白沉积，表明NAC可能为HCCAA提供一种预防策略。
ClinicalTrialsRegister.eu标识符：2017-004776-56。
