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A61k9/00 (2006.01) A61k9/51 (2006.01) ( (51) International Patent Classification: TR), OAPI (BF, BJ, CF, CG, Cl, CM, GA, GN, GQ, GW, A61K9/00 (2006.01) A61K 31/19 (2006.01) KM, ML, MR, NE, SN, TD, TG). A61K9/51 (2006.01) A61P 1/00 (2006.01) Published: (21) International Application Number: — with international search report (Art. 21(3)) PCT/US20 19/0566 11 (22) International Filing Date: 16 October 2019 (16. 10.2019) (25) Filing Language: English (26) Publication Language: English (30) Priority Data: 62/746,149 16 October 2018 (16. 10.2018) US 62/796,576 24 January 2019 (24.01.2019) US 62/855,915 31 May 2019 (3 1.05.2019) US (71) Applicant: MASSACHUSETTS INSTITUTE OF TECHNOLOGY [US/US]; 77 Massachusetts Avenue, Cambridge, MA 02139 (US). (72) Inventors; and (71) Applicants: ENG, George [US/US]; 2 Hawthorne Place, Apt 3D, Boston, MA 021 14 (US). WANG, Fang [CN/US]; 7 Dodge St, Apt 3, Cambridge, MA 02139 (US). (72) Inventors: YILMAZ, Omer; 169 Monsignor Hwy, #312, Cambridge, MA 02141 (US). CHENG, Chia-Wei; 350 Pearl Street, Unit #1, Cambridge, MA 02139 (US). (74) Agent: BALICKY, Eric, M. et al. ;HAMILTON, BROOK, SMITH & REYNOLDS, P.C., 530 Virginia Rd, P.O. Box 9133, Concord, MA 01742-9133 (US). (81) Designated States (unless otherwise indicated, for every kind of national protection available) : AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IR, IS, JO, JP, KE, KG, KH, KN, KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, 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, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, 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, (54) Title: COMPOSITIONS AND METHODS FOR INDUCING INTESTINAL STEM CELL REGENERATION (57) Abstract: The present invention provides compositions comprising β-hydroxybutyrate, cyclic or linear β-hydroxybutyrate oligomers, and/or β-hydroxybutyrate ester derivatives, or pharmaceutically -acceptable salts thereof. In various embodiments, the com¬ positions are encapsulated by nanoparticles, such as nanoparticles comprising, e.g., poly(lactic-co-glycolic acid). In additional embod¬ iments, the invention provides methods of using such compositions to induce intestinal stem cell regeneration and/or treat radiation-in¬ duced intestinal damage in a subject. COMPOSITIONS AND METHODS FOR INDUCING INTESTINAL STEM CELL REGENERATION RELATED APPLICATIONS [0001] This application claims the benefit of .S . Provisional Application No. 62/855,915, filed on May 31, 2019, LT.S. Provisional Application No. 62/796,576, filed on January 24, 2019, and LT.S. Provisional Application No. 62/746,149, filed on October 16, 2018. The entire teachings of the above applications are incorporated herein by reference. GOVERNMENT SUPPORT [0002] This invention was made with government support under Grant No. R01 CA21 1184 awarded by the National Institutes of Health. The government has certain rights in the invention. BACKGROUND [0003] In the mammalian intestine, the actively cycling Lgr5+intestinal stem cells (ISCs) depend on the precise control of intrinsic regulatory programs that include the Wnt, Notch, and BMP developmental signaling pathways as well as extrinsic cues from their environment to dynamically remodel intestinal composition (Barker et al., 2007; Fre et al., 2005; Mihaylova et al., 2014; Nakada et al., 201 1; Qi et al., 2017; van der Flier et al., 2009; Yan et al., 2017). Lgr5+ISCs reside at the bottom of intestinal crypts and are nestled between Paneth cells in the small intestine (Sato et al., 201 1), deep secretory cells in the colon (Sasaki et al., 2016) and stromal cells throughout the small intestine and colon (Degirmenci et al., 2018; Shoshkes-Carmel et al., 2018), which comprise components of the ISC niche. These ISC niche cells elaborate myriad growth factors and ligands that determine ISC identity in part through modulation of these developmental pathways. In addition to these semi-static epithelial and stromal niche components, migratory immune cell subsets provide inputs that inform stem cell fate decisions through cytokine signaling based on external signals (Biton et al., 2018; Lindemans et al., 2015). [0004] Lgr5+ ISCs drive intestinal maintenance in homeostasis and regeneration in response to injury, such as from radiation-induced damage (Beumer and Clevers, 2016; Metcalfe et al., 2014). Accordingly, there is a need for compositions and methods that maintain or promote regeneration of Lgr5+ ISCs in the human gut in subjects suffering from such injuries. SUMMARY [0005] The present disclosure is based, in part, on the discovery that the ketone body, β- hydroxybutyrate (βΟΗΒ), governs a diet responsive metabolite signaling axis in Lgr5+ intestinal stem cells (ISCs) that modulates the Notch program to sustain intestinal sternness in homeostasis and regenerative adaptation. [0006] In one aspect, the present disclosure provides a composition comprising β- hydroxybutyrate, or a pharmaceutically-acceptable salt thereof, encapsulated by a nanoparticle. [0007] In another aspect, the present disclosure provides a composition comprising a 3- hydroxybutyrate ester derivative (e.g., glycerol-tri((/i)-3-hydroxybutyrate)), or a pharmaceutically-acceptable salt thereof, encapsulated by a nanoparticle. [0008] In a further aspect, the present disclosure provides a method of inducing intestinal stem cell regeneration in a subject, comprising administering an effective amount of β- hydroxybutyrate, or a pharmaceutically-acceptable salt thereof, to the subject. [0009] In yet another aspect, the present disclosure provides a method of inducing intestinal stem cell regeneration in a subject, comprising administering an effective amount of a 3-hydroxybutyrate ester derivative (e.g., glycerol-tri((/i)-3-hydroxybuty rate)), or a pharmaceutically-acceptable salt thereof, to the subject. [0010] In another aspect, the present disclosure provides a method of treating radiation- induced intestinal damage in a subject, comprising administering an effective amount of β- hydroxybutyrate, or a pharmaceutically-acceptable salt thereof, to the subject. [0011] In an additional aspect, the present disclosure provides a method of treating radiation-induced intestinal damage in a subject, comprising administering an effective amount of a 3-hydroxybutyrate ester derivative (e.g., glycerol-tri((f?)-3-hydroxybutyrate)), or a pharmaceutically-acceptable salt thereof, to the subject. [0012] In another aspect, the present disclosure provides a method of treating radiation- induced intestinal damage in a subject, comprising administering an effective amount of a histone deacetylase (HDAC) inhibitor to the subject. BRIEF DESCRIPTION OF THE DRAWINGS [0013] The foregoing will be apparent from the following more particular description of example embodiments, as illustrated in the accompanying drawings in which like reference characters refer to the same parts throughout the different views. The drawings are not necessarily to scale, emphasis instead being placed upon illustrating embodiments. [0014] FIGs. 1A-1F show HMGCS2 enriches for Lgr5+ intestinal stem cells (ISCs). FIG. 1A, Principal component analysis (PCA) for genes differentially expressed in gr -GFPlow 1 progenitors versus -GFP ISCs. Variance filtered by (p/pmaX)=5e-4; p=0. 14, q=0.28; plot/total:253/45578 variables. Axin2, axin-like protein 2; Hmgcs2, 3-Hydroxy-3- Methylglutaryl-CoA Synthase 2; Lgr5, Leucine-rich repeat-containing G-protein coupled receptor 5; Olfin4, Olfactomedin 4; n=4 mice (see also Table Sl). FIG. 1B, Mouse HMGCS2 protein expression by immunohistochemistry (IHC, brown) and Lgr5 expression by ISH (red). White-dashed line defines the intestinal crypt and black arrows indicate HMGCS2 + cells. The image represents one of 3 biological replicates. Scale bar, 50um. FIG. 1C, Human HMGCS2 protein expression by immunohistochemistry (IHC, brown). White- dashed line defines the intestinal crypt and black arrows indicate HMGCS2 + cells. The image represents one of 10 biological replicates. Scale bar, 50um. FIG. 1D, Stacked barplots show cell composition (%) of Hmgcs2 , Hmgcs2-expressing, Lgr5 and Lgr5-expressing intestinal epithelial cells. Numbers in parenthesis indicate the total number (n) of the noted cell populations. FIG. 1E, Hmgcs2-lacZ reporter construct where the lacZ-tagged allele reflects endogenous Hmgcs2 expression (left). Hmgcs2-lacZ expression (blue) in the small intestine (right). The image represents one of 3 biological replicates. Scale bar, 50um. FIG. 1F, Organoid-forming potential of flow-sorted Hmgcs2 acZ and Hmgcs2-lacZ+ crypt epithelial cells (7AAD EpCAM +) . 5,000 cells from each population was flow-sorted into matrigel with crypt culture media. Arrows indicate organoids and asterisk indicates aborted organoid debris. The numbers of organoids formed from plated cells were quantified at 5 day in culture. Data represent mean+/-s.e.m. **p<0.01. n=6 samples from 3 mice. Scale bar: 20 pm. [0015] FIGs. 2A-2L show loss of Hmgcs2 compromises ISC self-renewal and differentiation. FIG. 2A, Schematic of intestinal Hmgcs2 deletion in postnatal mice with Villin-CreERT2 (iKO) including the timeline for tamoxifen (TAM) injections and tissue collection. FIG. 2B, Kaplan-Meier survival curves of the WT and Hmgcs2-iKO mice starting the first day of tamoxifen injection. FIG. 2C, Body weights of WT and Hmgcs2-iKO mice. 15 days after first TAM injection. FIGs. 2D-F, Quantification (left) and representative images (right) of Olfactomedin 4+ (OLFM4 ) stem cells by IHC (FIG.
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