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(12) Patent Application Publication (10) Pub. No.: US 2007/0155661 A1 Kim (43) Pub US 2007 O155661A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2007/0155661 A1 Kim (43) Pub. Date: Jul. 5, 2007 (54) METHODS AND COMPOSITIONS FOR Related U.S. Application Data MODULATING THE DEVELOPMENT OF STEM CELLS (60) Provisional application No. 60/447,673, filed on Feb. 14, 2003. (75) Inventor: Seung Kim, Stanford, CA (US) Publication Classification Correspondence Address: FSH & NEAVE P GROUP (51) Int. Cl. ROPES & GRAY LLP A6II 38/18 (2006.01) ONE INTERNATIONAL PLACE A6II 38/17 (2006.01) BOSTON, MA 02110-2624 (US) GOIN 33/53 (2006.01) CI2P 2/06 (2006.01) (73) Assignee: THE BOARD of TRUSTEES of the A6II 38/28 (2006.01) LELAND STANDORD JUNOR UNI- (52) U.S. Cl. ............................ 514/12: 435/7.1: 435/69.1; VERSITY, PALO ALTO, CA (US) 530/303 (21) Appl. No.: 10/545,582 (57) ABSTRACT (22) PCT Filed: Feb. 17, 2004 The application provides, among other things, methods for increasing production of insulin in cells by contacting the (86). PCT No.: PCT/USO4/O4639 cells with a BMP family member and/or an activator of a BMP pathway. The application also provides methods for S 371(c)(1), increasing the production of beta cell precursor cells by (2), (4) Date: Nov. 28, 2006 contacting suitable cells with an inhibitor of a BMP pathway. Patent Application Publication Jul. 5, 2007 Sheet 1 of 7 US 2007/0155661 A1 FIGURE I Patent Application Publication Jul. 5, 2007 Sheet 2 of 7 US 2007/0155661 A1 ad C s O S 9 O C e Patent Application Publication Jul. 5, 2007 Sheet 3 of 7 US 2007/0155661 A1 |------ FIGURE 3 Patent Application Publication Jul. 5, 2007 Sheet 4 of 7 US 2007/0155661 A1 a . b A wW-.. ; s r w -A Y as: y s 16 IJ l Patent Application Publication Jul. 5, 2007 Sheet 5 of 7 US 2007/O155661 A1 Patent Application Publication Jul. 5, 2007 Sheet 6 of 7 US 2007/0155661 A1 • ~~~~-:::::::---~~~ .** FIGURE 6 Patent Application Publication Jul. 5, 2007 Sheet 7 of 7 US 2007/0155661 A1 14000 1OOOO 8000 4000 2000 2 3IN AT (s 2uMRA 100M RA Condition f 2 3 8 9 10 1 2 3 4 5 16 TT 8 FIGURE 7 US 2007/O 155661 A1 Jul. 5, 2007 METHODS AND COMPOSITIONS FOR ence of a BMP family member, such as a GDF8/GDF11 MODULATING THE DEVELOPMENT OF STEM subfamily member, or an activator of a BMP signaling CELLS pathway. Optionally, the BMP family member has one or more of the following characteristics: an amino acid CROSS-REFERENCE TO RELATED sequence that is at least 80% identical to a human GDF 11 APPLICATIONS or GDF8; ability to bind to an ActRIIA and/or ActRIIB receptor; an ability to increase Smad2 and/or Smad3 phos 0001. This application claims the benefit of the filing date phorylation in a stem cell; an ability to increases expression of U.S. Provisional Patent Application Ser. No. 60/447,673 of a gene that is positively regulated by Smada. In certain entitled “Methods and Compositions for Modulating the embodiments, the application provides methods for increas Development of Stem Cells' and listing Seung Kim as ing insulin production in a cell composition comprising stem inventor. The aforementioned provisional application is cells, the method comprising contacting the cell composition incorporated herein in its entirety. with a substance that stimulates an ActRIIA and/or ActRIIB signaling pathway. Activators of an ActRIIA and/or ActRIIB BACKGROUND signaling pathway may, for example, cause an increase in 0002 Diabetes mellitus (DM) is a major cause of mor Smad2 and/or Smad3 function or phosphorylation, or bidity and mortality worldwide, and incidence rates of type increase expression of a gene that is positively regulated by I and type II DM are increasing. In type I DM, destruction Smada. A BMP signaling pathway may be activated by of insulin-producing pancreatic islets leads to a prolonged causing overexpression of one or more positive regulators, illness often culminating in devastating multisystem organ such as Smad3, Smad3, or a BMP family member. A BMP failure and early mortality. Clinical trials demonstrate that signaling pathway may also be activated by inhibiting an tight glucose regulation can prevent the development of inhibitor, Such as noggin or chordin. Optionally, the cell diabetic complications, but attempts to achieve this regula composition comprises beta cell precursor cells. In certain tion by exogenous insulin administration are only partially embodiments, the cell composition is derived from embry Successful. onic stem cells that have been cultured in the presence of a 0003 Recent evidence suggests that islet cell transplan retinoid. tation with improved systemic immunosuppression may 0008. In certain embodiments, the application provides a provide a short-term durable remission in insulin require method for promoting the maturation of beta cell precursor ments in type I diabetics (Shapiro et al., 2000, NEngl J Med. cells, the method comprising contacting the beta cell pre 343: 230-238; Ryan et al., 2001, Diabetes 50: 710-719). cursor cells with a BMP family member. However, in DM and the vast majority of other human 0009. In certain aspects the application provides methods diseases amenable to treatment by tissue replacement, there for increasing the number of beta cell precursor cells in a cell is an extreme shortage of engraftable donor tissues. An composition by culturing the cell composition in the pres expandable source of tissues like human stem cells may ence of an antagonist of a BMP signaling pathway. The provide the best promise for tissue replacement strategies for antagonist of a BMP signaling pathway may be a secreted human diseases. polypeptide. Such as noggin, chordin or follistatin that binds 0004 Stem cells, including embryonic stem (ES) cells directly to a BMP family member. and various adult stem cells provide a promising potential 0010. In certain aspects, the application provides cell means for cell-replacement therapy in human diseases. Stem culture methods that employ sequential inhibition and acti cells may provide serve as an inexhaustible source for the vation of a BMP signaling pathway to obtain insulin production of replacement islets for transplantation in dia producing cells. For example, the cells may be cultured in betic humans. However, conditions to produce stably-dif the presence of a noggin, chordin or follistatin and then ferentiated functional insulin-producing cell compositions cultured in the presence of a BMP family member, such as (ICCs) with stem cells generally, and particularly ES stem cells, have not been developed to a clinically satisfactory a member of the GDF8/GDF11 subfamily. Optionally, the level. stem cells are islet precursor cells. 0011. In certain aspects, the application provides methods 0005 Methods to provide a renewable source of replace for ameliorating a condition associated with insufficient ment islets from stem cells could transform therapeutics in pancreatic function by administering a BMP family member, DM. Likewise, methods for stimulating the production of such as a GDF8/GDF 11 subfamily member, or an activator insulin producing cells in patients could also have significant of a BMP signaling pathway. Suitable subjects include those therapeutic effects. that have been diagnosed with type I or type II diabetes. SUMMARY 0012. In certain aspects, the application provides meth ods for increasing the production of beta cell precursor cells 0006. In certain aspects, the application provides meth in a subject, the method comprising administering to the ods for manipulating the development of insulin producing subject a substance that inhibits a BMP signaling pathway, cells and beta cell precursor cells by activating or antago Such as a noggin, chordin or follistatin. In some instances, nizing a BMP signaling pathway. Such methods may be sequential use of BMP pathway antagonists and activators applied, for example, to cultured cells or to subjects in need may be desirable. of improved pancreatic function. 0013 Insulin production in a subject may also be 0007. In certain embodiments, the application provides enhanced by administering a composition comprising insu methods for increasing the production of insulin in a cell lin producing cells produced according to a method of the composition by culturing the cell composition in the pres application. US 2007/O 155661 A1 Jul. 5, 2007 0014. In certain aspects, the application provides meth acinar cell volume in Gdf11 mice. Original magnification ods for assessing the effectiveness of a test agent for 4x(a,b), 16x(de) and 10x(gh) modulating the development of insulin producing cells. For example, a method may comprise: forming a mixture com 0018 FIG. 3. Defective pancreatic islet B-cell and C.-cell prising the test agent and a BMP pathway polypeptide; and numbers in Gdfl 1 deficient mice. (a-c) Immunohistochemi detecting binding between the test agent and the polypep cal detection of insulin (brown staining) at E17.5 in mice tide, wherein a test agent that binds the BMP pathway with the indicated genotypes. (d) Quantification of E17.5 polypeptide specifically and with an affinity of at least f-cell mass by point-counting morphometry in Gdf11" ", 10M has an increased likelihood of being effective for Gdf11", and Gdf11 pancreata. Data are shown as the modulating the development of insulin producing cells. In a average measurements from at least 4 mice of indicated further method embodiment, a cell is cultured with the test genotypeststandard error of the mean. (e-g) Immunohis agent; and an activity of a BMP signaling pathway is tochemical detection of glucagon (brown staining) at E17.5 detected, wherein a test agent that increases the activity of in mice with the indicated genotypes. (h-i) Pancreatic islet a BMP signaling pathway has an increased likelihood of cell expression of insulin (FITC, green) and glucagon (Cy3, being effective for increasing insulin production in a cell.
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