N-Acetylcysteine for Hereditary Cystatin C Amyloid Angiopathy
Year: 2025
Type: article
Study design: Clinical Trial
Abstract: Importance: 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. Objective: 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. Intervention: 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. Main Outcomes and Measures: 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. Results: 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. Conclusions and Relevance: 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. Trial Registration: ClinicalTrialsRegister.eu Identifier: 2017-004776-56.
Source: JAMA Neurology
Authors: Asbjorg Osk Snorradottir, Alvaro Gutierrez-Uzquiza, Paloma Bragado, Michael E. March, Charlly Kao, Enrico Bernardo Arkink, Solveig Jonsdottir, Arna Sigurdardottir, Helgi J. Isaksson, Hekla Liv Mariasdóttir, Olga Yr Bjorgvinsdottir, Natalia M. Kowal, Hugrun L. Heimisdottir, Astros Sverrisdottir, Astridur Palsdottir, Hans Tomas Bjornsson, Hakon Hakonarson
Institutions: University of Iceland, National University Hospital of Iceland, Universidad Complutense de Madrid, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos, Children's Hospital of Philadelphia, Johns Hopkins University, University of Pennsylvania
Language: English
Subfield: Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
OpenAlex ID: W4409002756