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(12) Patent Application Publication (10) Pub. No.: US 2017/0189384 A1 Penny Et Al US 201701. 89384A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2017/0189384 A1 Penny et al. (43) Pub. Date: Jul. 6, 2017 (54) REVERSING INTESTINAL INFLAMMATION (60) Provisional application No. 61/526,574, filed on Aug. BY INHIBITING RETNOIC ACID 23, 2011. METABOLISM Publication Classification (71) Applicant: THE BOARD OF TRUSTEES OF THE LELAND STANFORD JUNOR (51) Int. Cl. UNIVERSITY, STANFORD, CA (US) A6II 3/428 (2006.01) A6IR 9/00 (2006.01) (72) Inventors: Hweixian Leong Penny, Singapore A63L/484 (2006.01) (SG); Edgar George Engleman, (52) U.S. Cl. Atherton, CA (US); Nupur CPC ........ A6 IK3I/428 (2013.01); A61K 31/4184 Bhattacharya, Palo Alto, CA (US) (2013.01); A61K 9/0053 (2013.01) (21) Appl. No.: 15/464,010 (57) ABSTRACT (22) Filed: Mar. 20, 2017 An agent that increases local concentration of retinoic acid (RA) in the intestine through modifying enzymatic pathways Related U.S. Application Data involved in RA metabolism is administered in a dose effec (63) Continuation of application No. 14/962.782, filed on tive to inhibit or reverse production of inflammatory media Dec. 8, 2015, now Pat. No. 9,623,013, which is a tors by intestinal dendritic cells and thereby reduce intestinal continuation of application No. 13/592,180, filed on inflammation and tumor growth associated with intestinal Aug. 22, 2012, now Pat. No. 9.248,120. inflammation. Patent Application Publication Jul. 6, 2017. Sheet 1 of 16 US 2017/O189384 A1 Sigure : Figure C Figure 3. A Figure i8 8 Af -- W ApcMira' ApCyli?t -or CC: CO3 gure D SP. N. m S : & 3. : c Sl-246 a; Figure E Patent Application Publication Jul. 6, 2017. Sheet 3 of 16 US 2017/O189384 A1 Figure 3A figure 3B Rida Raid fai s s & g k 0.000 1.0 s 2. 2. 0.0005 8.5 s 5: 0.000 s'w *SS *S. s'* k s * s'* 0.0.s' s . Sir . S. S. BC sal C Epithelia: Ce:s Reich fa2 Raidia2 s is 0.08 ; : s: s s as2 y g S S. s 0.02 ags. S$ s -SY - 3. S-P sp: C. Epiteia: cells Raiff as Raidi fa3 .334 is 63 c : 3 3. 0.00 0.2 4. 4. a 0.4 0.80; s s f so - S- S- * S. s S- f s s'8s s r & - s e & s S S-3 spi C Epithetia ceils t Cibot Figure 3C .4 Cibp1 s (028 5 8 (.830 a 0.63 s sx g O. 6. g 0.02 0830 S. is {005 : good R- o,00- St S. s k S. s 3. s a. 3. S. 8. s s NXs S & S SC spidC Epiheia ces Patent Application Publication Jul. 6, 2017. Sheet 4 of 16 US 2017/O189384 A1 Normal Colon FAR Pt FAP p2 Figure kA a Figure 4:3 Figure 4E. Patent Application Publication Jul. 6, 2017. Sheet 5 of 16 US 2017/O189384 A1 Figure 5A Figure 5. % Body Wt A over time Survival curves --a 1. ...; is 50 - S 3G •"; : 60 | &. 40 g 4 o is go 3. s O r { 8 2 3 4 5 - ? 8 S 22 22 3. weeks S -38 Figare 5C Figure 5: 8. hieratocrit over tire 5 A cover tire -- X & 3. is 33 3. -8 35 & ARS - Base 350 - x A2C8* - &osigliazone 30 S.ar 3 :x AC*.A Wita&etees: deficist i:33: *: ":- Wy - EaseKosigitazo,8 O 8 :* - Ciscox:8. O *X: i -- y - $8,388 858 to 1; 13 is a 5 is 17 is 1920.23%weeks: is gig weeks Figure 58 Figure 5 % Boey it & over time seaso over tire Figure 56 Agye inse afaese arosexie a i.arcised: 4 3. s 30 e 40 g s e; Or 10 1 2 --- 3 4. 8 -3 *:: Week s: 8 x8:3-M, s “x. f : 8 S ; ; 2 3 4: 15 S-23 “x. i sisteks as &:-----& :: S-888: 88s. 3 -3 re-reelerate &: 888,828 Polyp count 028 9 to 1 12 3 4 5 &-40 liarzai 25 Figure 5: eas Figure 5- Xy Wa Retiroic acid {} . as 2. 8 i &:*:8:3& 8 * 8.* É 15 8::::::::::s d 60is x- ss ... 40 i. 8."t : . 2. & O 2. & K & 2 SS. &; y: 3' o see yes s& S$ & -S $*sy Patent Application Publication Jul. 6, 2017. Sheet 6 of 16 US 2017/O189384 A1 Figure 6 Proposed Model widtype-steady-state APC - Adenoma progression 8 Rierarce Chronic infantation Sinai intestine Polyp. lumen : E888 Patent Application Publication Jul. 6, 2017. Sheet 7 of 16 US 2017/O189384 A1 s Patent Application Publication Jul. 6, 2017. Sheet 8 of 16 US 2017/O189384 A1 Figure 8A Figure 8B SP mN/PP S-P 2OOM uM 5uM WT S-LPDC : eyo : C X o: l APCMin'+ S-LPDC CFSE --------> & CFSE OOM ISO MSCR 10M SC CD4+ sorted CD25 Agdose Day 0 CFSE-labeled W S-POC APCMini+ S-LPDC CFSE Figure 8C Patent Application Publication Jul. 6, 2017. Sheet 9 of 16 US 2017/O189384 A1 Figure 9A Figure 98 AC 2. Af s wf 3. 4.5 AFC* 3.aa . & s a. 8 g a. : 3. 8.5 . s , s * &s is 3. s S& s S. s s Eithetia ceilis 3. SC . - if (8 S. i S. yar 2: Exck: AR- 8 A:s & 604 S: g 0.92 s: s & . ne s S.& * s s S- C spx 3C ::iteia: ce:s Patent Application Publication Jul. 6, 2017. Sheet 10 of 16 US 2017/0189384 A1 Figure (A Figure 38 Retiny Esters Retic SE 2. g s aa l :- s:: Patent Application Publication Jul. 6, 2017. Sheet 11 of 16 US 2017/O189384 A1 ??eun61-) Patent Application Publication Jul. 6, 2017. Sheet 12 of 16 US 2017/0189384 A1 Figure 12 % Body Wt A over time 83 S3 <- W - Base 8 <- W - Rosiglitazone 8- W - Celecoxii. 33 x W - Wit A deficient . -23 3. Patent Application Publication Jul. 6, 2017. Sheet 13 of 16 US 2017/0189384 A1 Figure 13 Cox2 O.2O O. 5 O. 10 O.05 Patent Application Publication Jul. 6, 2017. Sheet 14 of 16 US 2017/O189384 A1 88: igire 4C gue 48 Figure 4D ? Sisks 8 3. 8.3:...: 3 & figure 4E W + Liarozole CD4 Figure E4F Patent Application Publication Jul. 6, 2017. Sheet 15 of 16 US 2017/0189384 A1 Figure 15 & Patent Application Publication Jul. 6, 2017. Sheet 16 of 16 US 2017/0189384 A1 US 2017/O 189384 A1 Jul. 6, 2017 REVERSING INTESTINAL INFLAMMATION differentiation. In addition to its ability to support the BY INHIBITING RETNOIC ACID development of T17 cells, IL-23 induces the secretion of METABOLISM IL-17 by non-T-cells in an inflammatory environment, and both T cells and monocytes serve as sources of increased CROSS REFERENCE expression in the mucosa of IBD patients. 0001. This application claims benefit and is a Continua 0007 An understanding and manipulation of inflamma tion of application Ser. No. 14/962,782 filed Dec. 8, 2015, tory cells in the gut is of great interest. The present invention which claims the benefit and is a Continuation of application addresses this issue. Ser. No. 13/592,180, filed Aug. 22, 2012, now U.S. Pat. No. 9,248,120, issued Feb. 2, 2016, which claims benefit of U.S. SUMMARY OF THE INVENTION Provisional Patent Application No. 61/526,574, filed Aug. 0008 Methods are provided for reducing intestinal 23, 2011, which applications are incorporated herein by inflammation, particularly chronic inflammation, and tumor reference in their entirety. growth precipitated by intestinal inflammation. In the meth ods of the invention, an effective dose of an agent is FEDERALLY SPONSORED RESEARCH AND provided to the individual, where the agent increases local DEVELOPMENT concentration of retinoic acid (RA) in the intestine through 0002 This invention was made with Government support modifying enzymatic pathways involved in RA metabolism. under contract CA141468 awarded by the National Institutes 0009. In some embodiments, an inhibitor of CYP26A1 is of Health. The Government has certain rights in the inven administered in a dose effective form to neutralize a pre tion. existing inflammatory environment, prevent the develop ment of inflammation, or maintain the tolerogenic functions BACKGROUND OF THE INVENTION of intestinal dendritic cells that maintain intestinal tolerance by inducing Treg formation. Alternatively, an agent that 0003 Pathological inflammation is emerging as an under increases activity of retinaldehyde dehydrogenase or retinol lying mechanism for numerous diseases. For example, the dehydrogenase may be administered in a dose effective to major forms of idiopathic IBD, ulcerative colitis and neutralize or prevent inflammation in the intestine. The Crohn's disease are chronic inflammatory disorders of the appropriate dose may be determined by evaluating the effect gastrointestinal tract. Animal studies have shown that of the agent on functions of intestinal dendritic cells, for chronic intestinal inflammation precipitates as well as propa example by monitoring synthesis of cytokines such as IL-23 gates tumor growth. and IL-17, or by overall analysis of intestinal inflammation. 0004. A number of sentinel cell populations in the intes The methods of the invention exclude administration of tinal mucosa continuously monitor luminal microbes and retinoic acid directly. other antigens. Among the Subsets of antigen-presenting 0010 Dendritic cells are shown to be reprogrammed due cells, myeloid-derived dendritic cells are a dominant sub to local loss of the vitamin A metabolite, retinoic acid (RA), type in the intestinal lamina propria and show considerable which occurs as a result of insufficient retinaldehyde dehy functional plasticity depending on the location, state of drogenase and an overabundance of the transcriptional co maturation, and stage of inflammation.
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