N-acetylcysteine attenuates aortic stenosis progression by inhibiting shear-mediated TGF-beta activation and signaling
Inventors
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Assignees
Member
Oklahoma Medical Research FoundationFounded in 1946, this independent nonprofit biomedical research institute conducts basic, translational, and clinical research in critical areas such as heart disease, cancer, autoimmune, and neurodegenerative diseases. Its mission focuses on understanding biological mechanisms and advancing diagnostics and therapeutics. Activities include conducting clinical trials, managing a patent portfolio, commercializing biotechnologies, and supporting the biotech community. Research efforts are funded by grants and philanthropy, and the institute hosts advanced facilities, interdisciplinary research teams, and collaborations with academia and industry.
Founded in 1946, this independent nonprofit biomedical research institute conducts basic, translational, and clinical research in critical areas such as heart disease, cancer, autoimmune, and neurodegenerative diseases. Its mission focuses on understanding biological mechanisms and advancing diagnostics and therapeutics. Activities include conducting clinical trials, managing a patent portfolio, commercializing biotechnologies, and supporting the biotech community. Research efforts are funded by grants and philanthropy, and the institute hosts advanced facilities, interdisciplinary research teams, and collaborations with academia and industry.
Publication Number
US-11752122-B2
Publication Date
2023-09-12
Expiration Date
Abstract
The present disclosure relates to compositions of N-acetylcysteine for use in treating aortic stenosis. Methods of treating aortic stenosis in a subject comprising administering to said subject an effective amount of N-acetylecysteine (NAC) or other thiol-reactive compound, or agents that inhibit TGF-Beta activation and/or signaling.
Core Innovation
The invention discloses a method of treating aortic valve stenosis by administering N-acetylcysteine (NAC) or other thiol-reactive agents that inhibit shear-mediated activation of latent TGF-β1 and downstream Smad signaling. High wall shear stress activates platelet-derived latent TGF-β1, which induces valvular endothelial cell-to-mesenchymal transition and collagen-producing myofibroblasts via p-Smad2, driving aortic stenosis.
The disclosure introduces a robust Ldlr−/− Apob100/100 high-fat-diet mouse model and a modified echocardiographic view for early-stage aortic stenosis detection, and reports that NAC blocks shear-dependent TGF-β1 activation in vitro and in vivo. Short-term NAC treatment attenuates progression of mild–severe aortic stenosis, and NAC has no additional effect in platelet‑TGF‑β1 knockout mice supporting a platelet‑TGF‑β1‑specific mechanism. Additional dosing, formulation, biomarker, and adverse effect details are [procedural detail omitted for safety].
Claims Coverage
The claims include one independent claim with one principal inventive feature.
Administration of N-acetylcysteine (NAC)
Administering to said subject N-acetylecysteine (NAC) [procedural detail omitted for safety].
The independent claim principally claims a method of treating aortic valve stenosis by administering N-acetylcysteine at a defined dose range [procedural detail omitted for safety].
Stated Advantages
Slowing, mitigating, or preventing progression of aortic valve stenosis.
Blocking shear-mediated activation of platelet-derived latent TGF-β1 and downstream p-Smad2 signaling to reduce VECMT and myofibroblast-driven collagen production.
Short-term NAC treatment attenuates progression of mild–severe aortic stenosis.
Documented Applications
Treating aortic valve stenosis in a human subject by administering N-acetylcysteine (NAC), including attenuation of mild–severe disease progression with short-term NAC treatment and slowing, mitigating, or preventing progression.
Treatment of aortic valve stenosis arising from specified etiologies including age-related progressive fibrosis, calcification of a congenital bicuspid aortic valve, unicuspid valves, acute rheumatic fever, post-inflammatory responses, Fabry disease, systemic lupus erythematosus, Paget disease, high blood uric acid levels, infection, mixed aortic valve diseases (including aortic regurgitation and aortic valve fusion after LVAD implantation), and hypertension-induced cardiac pressure overload.
Use of a modified echocardiographic view for early-stage aortic stenosis detection.
Monitoring biomarkers and treatment refinement [procedural detail omitted for safety].
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