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

Detailed Technology Description
Thetechnology is a method of blockading CTPS1 as a target for therapeutics intreating neointima-related disorders. Specifically, the invention aims to be vascularsmooth muscle specific anti-proliferative drugs for the next-generation drugeluting stents. Vascular remodeling as a result of smooth muscle cell (SMC)proliferation and neointima formation is a major medical challenge incardiovascular intervention. However, antineointima drugs often indistinguishablyblock re-endothelialization, an essential step toward successful vascularrepair, because of their nonspecific effect on endothelial cells (ECs). Analternative treatment is then highly desirable.
*Abstract

Using ratballoon injury and mouse wire injury models, the investigators identified CTPsynthase 1 (CTPS1) as a target for therapeutics in treating neointima-relateddisorders. CTPS1 was induced in proliferative SMCs in vitro and neointima SMCsin vivo. Blockade of CTPS1 expression by small hairpin RNA or activity bycyclopentenyl cytosine suppressed SMC proliferation and neointima formationwhile having much less effect on EC proliferation. Small molecule blockade ofCTPS1 in vivo sustained the re-endothelialization as a result of induction ofCTP synthesis salvage pathway enzymes nucleoside-diphosphate kinase A and B inECs. Diphosphate kinase B seemed to preserve EC proliferation via use ofextracellular cytidine to synthesize CTP. The investigators have uncovered a fundamental difference in CTPbiosynthesis between SMCs and ECs during vascular remodeling, providing astrategy by using cyclopentenyl cytosine or other CTPS1 inhibitors toselectively block SMC proliferation without disturbing or even promotingre-endothelialization for effective vascular repair after injury. The inventiondirectly addresses three issues: impaired re-endothelialization following stentplacement; indiscriminate targeting of both EC and VSMC proliferation; and intimalhyperplasia.

References and Intellectual Property

 

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

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