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CTP synthase 1 (CTPS1) inhibitors for treating neointima-related disorders

Details

Project TitleCTP synthase 1 (CTPS1) inhibitors for treating neointima-related disorders
Track Code2021
Short Description

The technology is a method of blockading CTPS1 as a target for therapeutics in treating neointima-related disorders. Specifically, the invention aims to be vascular smooth muscle specific anti-proliferative drugs for the next-generation drug eluting stents. Vascular remodeling as a result of smooth muscle cell (SMC) proliferation and neointima formation is a major medical challenge in cardiovascular intervention. However, antineointima drugs often indistinguishably block re-endothelialization, an essential step toward successful vascular repair, because of their nonspecific effect on endothelial cells (ECs). An alternative treatment is then highly desirable.

Abstract

Using rat balloon injury and mouse wire injury models, the investigators identified CTP synthase 1 (CTPS1) as a target for therapeutics in treating neointima-related disorders. CTPS1 was induced in proliferative SMCs in vitro and neointima SMCs in vivo. Blockade of CTPS1 expression by small hairpin RNA or activity by cyclopentenyl cytosine suppressed SMC proliferation and neointima formation while having much less effect on EC proliferation. Small molecule blockade of CTPS1 in vivo sustained the re-endothelialization as a result of induction of CTP synthesis salvage pathway enzymes nucleoside-diphosphate kinase A and B in ECs. Diphosphate kinase B seemed to preserve EC proliferation via use of extracellular cytidine to synthesize CTP.  The investigators have uncovered a fundamental difference in CTP biosynthesis between SMCs and ECs during vascular remodeling, providing a strategy by using cyclopentenyl cytosine or other CTPS1 inhibitors to selectively block SMC proliferation without disturbing or even promoting re-endothelialization for effective vascular repair after injury. The invention directly addresses three issues: impaired re-endothelialization following stent placement; indiscriminate targeting of both EC and VSMC proliferation; and intimal hyperplasia.

References and Intellectual Property

 

Rui Tang, Xiao-Bing Cui, Jia-Ning Wang and Shiyou Chen: CTP synthase, a smooth muscle-sensitive therapeutic target for effective vascular repair. Arteriosclerosis, Thrombosis, and Vascular Biology (ATVB), 33(10):2336-44, 2013 and associated editorial

 
Tagstherapeutic, Cardio vascular disorders (CVD), Synthase, hyperplasia
 
Posted DateNov 14, 2017 11:55 AM

People

Name
Cory Acuff

Files

File Name Description
2021 Tang CA.doc None Download