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(12) Patent Application Publication (10) Pub. No.: US 2014/0274766A1 Abramson Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2014/0274766A1 Abramson Et Al US 20140274766A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2014/0274766A1 Abramson et al. (43) Pub. Date: Sep. 18, 2014 (54) METHODS OF USING F-SPONDINASA (52) U.S. Cl. BOMARKER FOR CARTILAGE CPC .......... CI2O I/6883 (2013.01); G0IN33/6893 DEGENERATIVE CONDITIONS AND BONE (2013.01); G0IN33/6887 (2013.01); G0IN DISEASES 33/5041 (2013.01) USPC ............ 506/9; 435/6.12:435/6.11: 435/7.92; (71) Applicants: Steven B. Abramson, Rye, NY (US); 436/501; 435/7.93; 435/7.94; 435/29: 435/7.4: Mukundan Attur, Woodside, NY (US); 435/6.13 Glyn Palmer, Brooklyn, NY (US); Ashok Amin, Union, NY (US) (57) ABSTRACT (72) Inventors: Steven B. Abramson, Rye, NY (US); Methods for identifying subjects having, or at risk for devel Mukundan Attur, Woodside, NY (US); oping, osteoarthritis or other cartilage degenerative condi Glyn Palmer, Brooklyn, NY (US); tions by measuring levels of expression of F-spondin are Ashok Amin, Union, NY (US) provided. Assays, kits and methods for determining and assaying the presence of F-spondin in individual patients are (21) Appl. No.: 14/155.491 disclosed. Oligonucleotide probes and primers for use in the assays, kits and methods are described. Assays and methods (22) Filed: Jan. 15, 2014 are disclosed for identifying candidate compounds that O O modulate F-spondin levels of expression and/or function or Related U.S. Application Data for determining and evaluating an individual’s response to (63) Continuation of application No. 12/455.296, filed on drugs and therapeutic agents, are provided. The invention May 29, 2009, now abandoned. further relates to the modulation of F-spondin, particularly the inhibition of F-spondin, for increasing or stimulating bone Publication Classification formation and/or growth and mediating the alleviation of bone disease, disorders or conditions. The use of F-spondin, (51) Int. Cl. an active fragment thereof, or a modulator thereof for enhanc CI2O I/68 (2006.01) ing cartilage repair or preventing or treating cartilage degen GOIN33/50 (2006.01) eration, degenerative diseases or arthritic conditions is also GOIN33/68 (2006.01) provided. Patent Application Publication Sep. 18, 2014 Sheet 1 of 28 US 2014/027476.6 A1 IeuuuoNu?sau39pessºudxEÁI?e?ueue??qgo6u?u??snIO 36e???ue:OVOpue leuuuON Patent Application Publication Sep. 18, 2014 Sheet 2 of 28 US 2014/0274766A1 FIGURE 1B tial Expression of F-spondi i. to :: Patent Application Publication Sep. 18, 2014 Sheet 3 of 28 US 2014/027476.6 A1 FIGURE 1C Differential Expression of F-spondin in Normal and OA Cartilage (GPCR) Patent Application Publication Sep. 18, 2014 Sheet 4 of 28 US 2014/027476.6 A1 FIGURE 2 Patent Application Publication Sep. 18, 2014 Sheet 5 of 28 US 2014/027476.6 A1 FIGURE3 lesion Non-lesion Non-lesion F-spondin (RAb) Collagen Patent Application Publication Sep. 18, 2014 Sheet 6 of 28 US 2014/027476.6 A1 FIGURE 4 Elevated Expression of F-spondin in surgical model of Rat OA sham contralateral ipsilateral Patent Application Publication Sep. 18, 2014 Sheet 7 of 28 US 2014/027476.6 A1 FIGURE 5A Patent Application Publication Sep. 18, 2014 Sheet 8 of 28 US 2014/027476.6 A1 FIGURE SB Resting Froliferative Maturing Hypertrophic Gatcfied Patent Application Publication Sep. 18, 2014 Sheet 9 of 28 US 2014/027476.6 A1 Patent Application Publication Sep. 18, 2014 Sheet 10 of 28 US 2014/027476.6 A1 0 0 Adoo up uods 000000Z|. 0000000}, 0000008 0000009 Adoo uebeuffv Patent Application Publication Sep. 18, 2014 Sheet 11 of 28 US 2014/027476.6 A1 FIGURE 8 Patent Application Publication Sep. 18, 2014 Sheet 12 of 28 US 2014/027476.6 A1 u?puods--.Jos?onu?suolosno?ue/\ Patent Application Publication Sep. 18, 2014 Sheet 13 of 28 US 2014/027476.6 A1 (ds)aouenbes?eußis Patent Application Publication Sep. 18, 2014 Sheet 14 of 28 US 2014/027476.6 A1 3)Koopuol?oueuun?u?u?puods--,gouo?ssaudxæeue6sueul seu36olloqeueSnoqueapºonpu?ZIºzoeu||||30 Adoo ueBeoso edAL # Adoo upluods 00008-$0+E"| Adoo ueoeffiv Patent Application Publication Sep. 18, 2014. Sheet 15 of 28 US 2014/027476.6 A1 FIGURE 11 1 O O Control Convec R1 Ab FS Sup FS+-Con FS FS+ LM609 Sup Sup R1 LM609 R1-Rabbitantibody raised against TSR domains (3-6) of F-spondin LR609-integrin ov33 blocking antibody. Patent Application Publication Sep. 18, 2014 Sheet 16 of 28 US 2014/027476.6 A1 () 9 efeJeo go fff)d g-seo (9 w C O X c) () o t b 9 C O S CO L Cen O V C) L () H l O O w 2 w 9 efereo Jo f/6d g--Semav C Patent Application Publication Sep. 18, 2014 Sheet 17 of 28 US 2014/027476.6 A1 CIZ |-00 asee?ouduwoux'un &,ALIAILOV 949L Patent Application Publication Sep. 18, 2014 Sheet 18 of 28 US 2014/027476.6 A1 1000 C O O SD re o 1 OO -- Col X X y CD - A-AP CD s --- MMP-13 O) g 1 O -- F-spondin t CD 1. F--- - - - - - - - - - - -N.D increasing Maturation (RA stimulation) Patent Application Publication Sep. 18, 2014 Sheet 19 of 28 US 2014/027476.6 A1 Patent Application Publication Sep. 18, 2014 Sheet 20 of 28 US 2014/027476.6 A1 c 2 1s 25 3 a 20 T is a 15 .S nS 10 C S.9 5 O 35 1OO Retinoic acid (nM) Patent Application Publication Sep. 18, 2014 Sheet 21 of 28 US 2014/027476.6 A1 1600 O C O.O1 WS Ctrl 12OO 800 400 Ctrl FS LAP (10 LAP (100 FS+ LAP FS + LAP (lug/ml) ng/ml) ng/ml) (10) (100) Patent Application Publication Sep. 18, 2014 Sheet 22 of 28 US 2014/027476.6 A1 1600 Big Vector Ctrl epF-Spondin pz 0.01 2 12OO Co 800 m 400 Patent Application Publication Sep. 18, 2014 Sheet 23 of 28 US 2014/0274766A1 FIGURE 19 A Resting Proliferative Calcified mRNA Levels in Growth Plate Chondrocytes (% Change from PROLIFERATIVE) GENE PROLIFERATIVE HYPERTROPHC CALCIFIED Type if Collagen Type X Collagen 23 93 F-spondin Type Collagen Patent Application Publication Sep. 18, 2014 Sheet 24 of 28 US 2014/027476.6 A1 FIGURE 20 2O Ctrl FS Anti-FS Patent Application Publication Sep. 18, 2014 Sheet 25 of 28 US 2014/027476.6 A1 FIGURE 21 mRNA Levels in Chick Sternal Chondrocytes (% Change from RA0) Patent Application Publication Sep. 18, 2014 Sheet 26 of 28 US 2014/027476.6 A1 FIGURE 22 B Ctrl FS AP Col X Col MMP-13 Runx-2 Patent Application Publication Sep. 18, 2014 Sheet 27 of 28 US 2014/027476.6 A1 FIGURE 23 A B 250 RAO Se Thronosponstreat SR s 200 RA100 Reelin Hspondin123456 5. m-ma-gefs a. Sg 150 -g) FS8 100 is 50 O Ctrl FS FS6 C Ctrl Anti-FS (TSR domain) Anti-FS (Spondin domain) O 10 35 1OO Patent Application Publication Sep. 18, 2014 Sheet 28 of 28 US 2014/027476.6 A1 FIGURE 24 A AP F-spondin MMP-13 B Conditioned media 4. Conditioned media - TGFB Vec Ctrl FS1 US 2014/027476.6 A1 Sep. 18, 2014 METHODS OF USING F-SPONDINASA cells that are responsible for manufacturing the type II col BOMARKER FOR CARTLAGE lagen and proteoglycans, both of which form the cartilage DEGENERATIVE CONDITIONS AND BONE matrix. The cartilage matrix has physical-chemical properties DISEASES that allow for saturation of the matrix with water. In the absence of osteoarthritis, articular cartilage has exceptional CROSS-REFERENCE TO RELATED wear characteristics and allows for almost frictionless move APPLICATIONS ment between the articulating cartilage surfaces. 0001. The present application is a continuation-in-part 0004 Chondrogenesis is the earliest well-orchestrated application claiming the priority of copending application and controlled phase of skeletal development, involving mes PCT/US2007/024658, filed Nov. 30, 2007, which in turn enchymal cell recruitment and migration, condensation of claims priority from provisional application Ser. No. 60/631, progenitors, chondrocyte proliferation and differentiation, 828, filed Nov.30, 2004, the disclosures of which are incor and maturation. This process is controlled exquisitely by porated by reference herein in their entirety. Applicants claim cellular interactions with the growth factors, Surrounding the benefits of 35 U.S.C. S 120 as to the PCT application and matrix proteins and other environmental factors that mediate priority under 35 U.S.C. S 119 as to the provisional applica cellular signaling pathways and transcription of specific tion. genes in a temporal-spatial manner. Production of and response to different growth factors are observed at all times FIELD OF THE INVENTION and autocrine and paracrine cell stimulations are key ele ments of the process. Particularly relevant is the role of the 0002. The invention relates to the identification and use of TGF-beta superfamily, and more specifically of the BMP F-spondin as a biomarker for chondrocyte hypertrophy and subfamily. Other factors include retinoids, FGFs, GH, and more specifically, as a biomarker for osteoarthritis and other IGFs. The growing evidences demonstrated that complicated cartilage degenerative conditions. The invention further cellular signaling language and informational content of relates to the identification of F-spondin as involved in endo chondrogenesis lie, not in an individual growth factor, but in chondral bone formation and growth and the modulation of the entire set of growth factors and others signals to which a F-spondin, particularly the inhibition of F-spondin, for cell is exposed. The ways in which growth factors exert their increasing or stimulating bone formation and/or growth and combinatorial effects are becoming clearer as the molecular mediating the alleviation of bone disease, disorders or con mechanisms of growth factors actions are being investigated.
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