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WO2015006500A2.Pdf (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 2015/006500 A2 15 January 2015 (15.01.2015) P O P C T (51) International Patent Classification: (72) Inventors: VON ANDRIAN, Ulrich, H.; 5 1 Randolph A61K 48/00 (2006.01) Road, Brookline, MA 02467 (US). THIRIOT, Aude; 125 Pleasant Street #607, Brookline, MA 02446 (US). (21) International Application Number: FAROKHZAD, Omid; 15 Laura Road, Waban, MA PCT/US20 14/04603 7 02468 (US). SHI, Jinjun; 380 Riverway, Unit #3, Boston, (22) International Filing Date: MA 021 15 (US). July 2014 (09.07.2014) (74) Agent: TRE ANNIE, Lisa, M.; Morse, Barnes-Brown & (25) Filing Language: English Pendleton, P.C., CityPoint, 230 Third Avenue, 4th Floor, Waltham, MA 0245 1 (US). (26) Publication Language: English (81) Designated States (unless otherwise indicated, for every (30) Priority Data: kind of national protection available): AE, AG, AL, AM, 61/844,372 ' July 2013 (09.07.2013) US AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, (71) Applicants: PRESIDENT AND FELLOWS OF HAR¬ BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, VARD COLLEGE [US/US]; 17 Quincy Street, Cam DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, bridge, MA 02138 (US). THE BRIGHAM AND WO¬ HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, MEN'S HOSPITAL, INC. [US/US]; 75 Francis Street, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, Boston, MA 021 15 (US). 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, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, [Continued on nextpage] (54) Title: ENDOTHELIAL CELL GENES AND USES THEREOF (57) Abstract: Disclosed herein are genes which are differentially ex pressed in venule endothelial cells (V - icrovascular segmentation ECs) compared to non-venule en dothelial cells (NV -ECs) and methods, compositions, kits, and agents relating to those genes. , Blood j Gas s y e supply exchange jadhesion | Heart - Aorta -» Arteries + Arterioies » Capilianes Venules » Veins ·+ V. cava < D a ) 2.S * 0.8 .06 + 0.05 - 0.001 + 0 001-0.0005 + 0 001-0.15 + 0.015-1.6 + 3.2 © Area (cm*). 5.3 + 20 + ΰ + S + 2700 + 100 + 18 o Hagen-Poiseuille'a Law: = 8 x i x x x r ©o Figure o GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, Published: UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, without international search report and to be republished TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, upon receipt of that report (Rule 48.2(g)) 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, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG). ENDOTHELIAL CELL GENES AND USES THEREOF RELATED APPLICATIONS [0001] This application claims the benefit of U.S. Provisional Application Serial No. 61/844,372, filed July 9, 2013, the teachings of which are incorporated herein by reference in their entirety. GOVERNMENT SUPPORT [0002] This invention was made with government support under ROl AI069259 and POl AI078897 awarded by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health. The government has certain rights in the invention. BACKGROUND OF THE INVENTION [0003] Current anti-inflammatory drugs, such as corticoids, non-steroidal drugs and biologies, typically act systemically and thus affect both healthy and damaged tissues. Adverse side effects include gastrointestinal and renal effects as well as, in some cases, an increased susceptibility to infection linked to impaired leukocyte interactions with healthy tissue. There are currently no FDA-approved anti-inflammatory agents that selectively target the endothelium, much less tissue-specific vascular beds that promote inflammation. Accordingly, there is a need for agents (e.g., anti-inflammatory agents) that specifically target venular endothelium, either globally or in a tissue-specific manner. SUMMARY OF THE INVENTION [0004] In some aspects, disclosed herein is a method of modulating the venuleness of an endothelial cell, comprising contacting the endothelial cell with an effective amount of an agent that modulates expression of at least one gene that is differentially expressed in venule endothelial cells compared to non-venule endothelial cells. [0005] In some embodiments, modulating the venuleness of the endothelial cell comprises changing the endothelial cell from a venule endothelial cell to a non-venule endothelial cell. [0006] In some embodiments, the agent: (a) decreases expression of at least one gene exhibiting higher expression levels in venule endothelial cells compared to non- venule endothelial cells; (b) increases expression of at least one gene exhibiting lower expression levels in venule endothelial cells compared to non-venule endothelial cells; (c) increases expression of at least one gene exhibiting higher expression levels in non- venule endothelial cells compared to venule endothelial cells; or (d) decreases expression of at least one gene exhibiting lower expression levels in non-venule endothelial cells compared to venule endothelial cells. [0007] In some embodiments, the at least one gene exhibiting higher expression levels in venule endothelial cells compared to non-venule endothelial cells is selected from the group consisting of a gene, or combination of genes, listed in Table 1. In some embodiments, the at least one gene exhibiting lower expression levels in venule endothelial cells compared to non-venule endothelial cells is selected from the group consisting of a gene, or combination of genes, listed in Table 8. In some embodiments, the at least one gene exhibiting higher expression levels in non-venule endothelial cells compared to venule endothelial cells is selected from the group consisting of a gene, or combination of genes, listed in Table 8. In some embodiments, the at least one gene exhibiting lower expression levels in non-venule endothelial cells compared to venule endothelial cells is selected from the group consisting of a gene, or combination of genes, listed in Table 1. [0008] In some embodiments, modulating the venuleness of the endothelial cell comprises changing the endothelial cell from a non-venule endothelial cell to a venule endothelial cell. In some embodiments, the agent: (a) increases expression of at least one gene exhibiting higher expression levels in venule endothelial cells compared to non- venule endothelial cells; (b) decreases expression of at least one gene exhibiting lower expression levels in venule endothelial cells compared to non-venule endothelial cells; (c) decreases expression of at least one gene exhibiting higher expression levels in non- venule endothelial cells compared to venule endothelial cells; or (d) increases expression of at least one gene exhibiting lower expression levels in non-venule endothelial cells compared to venule endothelial cells. [0009] In some embodiments, the at least one gene exhibiting higher expression levels in venule endothelial cells compared to non-venule endothelial cells is selected from the group consisting of a gene, or combination of genes, listed in Table 1. In some embodiments, the at least one gene exhibiting lower expression levels in venule endothelial cells compared to non-venule endothelial cells is selected from the group consisting of a gene, or combination of genes, listed in Table 8. In some embodiments, the at least one gene exhibiting higher expression levels in non-venule endothelial cells compared to venule endothelial cells is selected from the group consisting of a gene, or combination of genes, listed in Table 8. In some embodiments, the at least one gene exhibiting lower expression levels in non-venule endothelial cells compared to venule endothelial cells is selected from the group consisting of a gene, or combination of genes, listed in Table 1. [0010] In some embodiments, the venuleness of the endothelial cells is modulated in a tissue-specific manner. In some embodiments, the endothelial cell is a skin endothelial cell. In some embodiments, the skin endothelial cell changes from a skin venule endothelial cell to a skin non-venule endothelial cell. [001 1] In some embodiments, the agent: (a) decreases expression of at least one gene exhibiting higher expression levels in skin venule endothelial cells compared to skin non-venule endothelial cells; (b) increases expression of at least one gene exhibiting lower expression levels in skin venule endothelial cells compared to skin non-venule endothelial cells; (c) increases expression of at least one gene exhibiting higher expression levels in skin non-venule endothelial cells compared to skin venule endothelial cells; or (d) decreases expression of at least one gene exhibiting lower expression levels in skin non-venule endothelial cells compared to skin venule endothelial cells. [0012] In some embodiments, the at least one gene exhibiting higher expression levels in skin venule endothelial cells compared to skin non-venule endothelial cells is selected from the group consisting of a gene, or combination of genes, listed in Table 2. In some embodiments, the at least one gene exhibiting lower expression levels in venule endothelial cells compared to non-venule endothelial cells is selected from the group consisting of a gene, or combination of genes, listed in Table 9. In some embodiments, the at least one gene exhibiting higher expression levels in non-venule endothelial cells compared to venule endothelial cells is selected from the group consisting of a gene, or combination of genes, listed in Table 9.
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