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WO 2014/186435 A2 20 November 2014 (20.11.2014) P O P C T

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WO 2014/186435 A2 20 November 2014 (20.11.2014) P O P C T (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2014/186435 A2 20 November 2014 (20.11.2014) P O P C T (51) International Patent Classification: KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, A61K 45/06 (2006.01) MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, (21) International Application Number: SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, PCT/US2014/037955 TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, (22) International Filing Date: ZW. 14 May 2014 (14.05.2014) (84) Designated States (unless otherwise indicated, for every (25) Filing Language: English kind of regional protection available): ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, (26) Publication Language: English UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, (30) Priority Data: TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, 61/823,163 14 May 2013 (14.05.2013) US EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, (71) Applicant: UNIVERSITY OF GEORGIA RESEARCH TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, FOUNDATION, INC. [US/US]; 634 Graduate Studies KM, ML, MR, NE, SN, TD, TG). Bldg., Athens, GA 30602 (US). Declarations under Rule 4.17 : (72) Inventors: CHEN, Shiyou; 1772 Brookhaven Drive, Bog- — as to applicant's entitlement to apply for and be granted a art, GA 30622 (US). TANG, Rui; 501 D W Brooks Drive, patent (Rule 4.1 7(H)) Athens, GA 30602 (US). — as to the applicant's entitlement to claim the priority of the (74) Agents: VORNDRAN, Charles et al; Pabst Patent Group earlier application (Rule 4.1 7(in)) LLC, 1545 Peachtree Street, NE, Suite 320, Atlanta, GA 30309 (US). — of inventorship (Rule 4.17(iv)) (81) Designated States (unless otherwise indicated, for every Published: kind of national protection available): AE, AG, AL, AM, — without international search report and to be republished AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, upon receipt of that report (Rule 48.2(g)) BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, — with sequence listing part of description (Rule 5.2(a)) HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, (54) Title: COMPOSITIONS AND METHODS FOR REDUCING NEOINTIMA FORMATION (57) Abstract: Compositions, devices, grafts and methods for reducing or preventing anti-neointima following cardiovascular injur ies and interventions are disclosed. The compositions, devices, and grafts typically include an effective amount of a CTP synthase 1 inhibitor to reduce proliferation of vascular smooth muscle cells, without substantial reducing the proliferation of endothelial cells. Methods of reducing neointima formation, accelerating re-endothelialization, and reducing restenosis in a subject using the composi tions, devices, and grafts are also disclosed. COMPOSITIONS AND METHODS FOR REDUCING NEOINTIMA FORMATION STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT This invention was made with Government Support under Agreement HL107526 awarded by the National Institutes of Health. The Government has certain rights in the invention. FIELD OF THE INVENTION The field of the invention is generally related to compositions, devices, and methods for enhancing recovery from vascular injury or surgery, and reducing morbidity and mortality associated with neointima and restenosis. BACKGROUND OF THE INVENTION Neointimal hyperplasia is one of the major obstacles limiting the long- term clinical efficiency of cardiovascular intervention including angioplasty, bypass, and transplantation arteriopathy, etc., (Degertekin, et al., Circulation., 106:1610-1613 (2002)). Neointima formation also contributes to the development and progression of several proliferative cardiovascular diseases such as atherosclerosis, hypertension, and diabetic vascular complications (Frank, et al., Curr. Opin. Lipidol., 15:523 (2004)). Under pathological conditions, vascular injury causes denudation of endothelial layer, which triggers a series of acute and chronic inflammatory responses characterized by the production of various different growth factors or inflammatory cytokines (Murakami, et al., Am J Physiol Lung Cell Mol Physiol., 272:L197-L202 (1997); Cotran, et al., J Am Soc Nephrol, 1:225-235 (1990)). Media layer smooth muscle cell (SMC) proliferation and migration in response to the injury- induced factors (such as platelet-derived growth factor, or PDGF) are essential events contributing to subsequent neointimal thickening (Fingerle, et al., Proc Natl Acad Set, 86:8412 (1989); Clowes, et a., Circ. Res., 56:139-145 (1985)) which eventually leads to vessel narrowing. Re-endothelialization halts neointima formation and initiates the successful vascular repair (Bauters, et al., Prog. Cardiovasc. Dis., 40:107-116 (1997); Kinlay, et al., Curr. Opin. Lipidol., 12:383 (2001)). However, currently available anti-neointimal drugs indiscriminately block the proliferation of both SMCs and endothelial cells (EC), leading to impaired re-endothelialization and prolonged wound healing process. There remains a need to develop an anti-proliferation strategy that is SMC-sensitive. Therefore, it is an object of the invention to provide compositions, devices, grafts, and methods of use thereof for reducing or preventing smooth muscle cell proliferation in a subject. It is a further object of the invention to provide compositions, devices, grafts, and methods of use thereof for promoting or enhancing re- enothelialization in a subject. It is also an object of the invention to provide compositions, methods, and devices, for reducing or preventing neointima formation, restenosis, or a combination thereof in a subject. SUMMARY OF THE INVENTION Compositions, devices, grafts, and methods for reducing or preventing anti-neointima following cardiovascular injuries and interventions are disclosed. The compositions, devices, grafts, and methods are effective to reduce proliferation of vascular smooth muscle cells, without substantial reducing the proliferation of endothelial cells. Accordingly, re-endothelialization is accelerated in treated subjects. The compositions typically include one or more CTP synthase 1 (CTPS 1) inhibitors in an amount effective to reduce proliferation of vascular smooth muscle cells (VSMC) in a subject. Preferably, the CTPS1 inhibitor reduces VSMC proliferation to a greater degree than the inhibitor reduces endothelial cell proliferation in the subject. In some embodiments, the composition does not substantially reduce the proliferation of endothelial cells in the subject. The compositions can include an effective amount of CTPS1 inhibitor to reduce neointima formation, permit or promote re-endothelialization, or a combination thereof at a site of vascular injury, a site of surgery, or a site of implantation of a vascular implant in the subject. Disclosed CTPS 1 inhibitors include nucleoside analogs such as cyclopentenyl cytosine, 3-deazauridine (3-DU), carbodine; glutamine analogs such as 6-diazo-5-oxo-L-norleucin (DON), and acivicin; functional nucleic acids designed to reduce expression of the CTPS1 gene or a gene product thereof; and polypeptides that reduces expression of the CTPS1 gene or a gene product thereof. In some embodiments the CTPS 1 inhibitor is antisense molecules, siRNA, miRNA, aptamers, ribozymes, triplex forming molecules, RNAi, or external guide sequences that target SEQ ID NO: 1, to gene editing compositions such as CRISPR/Cas, zinc finger nuclease, or TALEN compositions that target the CRPS1 gene and reduce or otherwise modify its expression. In some embodiments, the composition includes a delivery vehicle for delivering the CTPS1 inhibitor to vascular smooth muscle cells. The delivery vehicle can be, for example, nanoparticles, microparticles, micelles, synthetic lipoprotein particles, liposomes, or carbon nanotubes. The composition can include a targeting signal for enhancing delivery of the CTPS1 inhibitor to vascular smooth muscle cells. The targeting signal can facilitate binding of the composition to smooth muscle cells by targeting a cell surface ligand such as Tissue Factor or ν integrin; or the targeting signal can target the compositions to the vicinity of vascular injuries by binding to a marker of clots or thrombosis such as fibrin, gpIIb/IIIa, tissue factor/VIIA complex, activated clotting factor Xa, activated clotting factor IXa, or the fibrin condensation product d-dimer. The targeting signal can be operably linked to the CTPS1 inhibitor or to the delivery vehicle. Medical devices that are coated with or otherwise incorporate a composition including a CTPS 1 inhibitor are also disclosed. Disclosed devices include, but are not limited to, implants, needles, cannulas, catheters, shunts, stents, balloons, and valves. In a preferred embodiment, the device is a stent, for example, a drug eluting stent that elutes a composition including a CTPS 1 inhibitor. The CTPS1 inhibitor can increase re-endothelialization at the site of intervention and reduce or prevent stenosis or restenosis. Vascular grafts that are coated with or otherwise incorporate a composition including a CTPS 1 inhibitor are also disclosed. The vascular graft can be autologous, preserved autologous, allogeneic, xenogenic or synthetic. Ex vivo treatment of the graft with a CTPS 1 inhibitor prior
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