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US 2012/0315630 A1 Gong Et Al US 2012O315.630A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2012/0315630 A1 Gong et al. (43) Pub. Date: Dec. 13, 2012 (54) METHODS FOR DIAGNOSINGIRRITABLE (60) Provisional application No. 61/256,717, filed on Oct. BOWEL, SYNDROME 30, 2009, provisional application No. 61/264,588, filed on Nov. 25, 2009, provisional application No. (75) Inventors: Hua Gong, San Diego, CA (US); 61/326,176, filed on Apr. 20, 2010. Shui Long Wang, San Diego, CA O O (US); Sharat Singh, Rancho Santa Publication Classification Fe, CA (US) (51) Int. Cl. GOIN 33/566 (2006.01) (73) Assignee: Prometheus Laboratories Inc., CI2O I/68 (2006.01) San Diego, CA (US) GOIN 33/573 (2006.01) (52) U.S. Cl. ........ 435/6.11: 436/501; 435/7.4; 435/7.92; (21) Appl. No.: 13/441,658 435/6.12 (57) ABSTRACT (22) Filed: Apr. 6, 2012 The invention provides novel biomarkers, kits, and methods O O of diagnosing, prognosing, and Subtyping IBS. Also provided Related U.S. Application Data are methods for aiding in the diagnosis of irritable bowel (63) Continuation of application No. PCT/US 10/54810, syndrome by detecting the serum level of novel IBS biomar filed on Oct. 29, 2010. kers identified herein. Patent Application Publication Dec. 13, 2012 Sheet 1 of 31 US 2012/0315630 A1 Optimize the Coating Ab Dose response Curwe of unan tryptase with Different Annex tart of Coating Antibody 1000 * is agiri toooo & 3 agi: 9000 8000 rooo sooo 4000- & 3000 i.cg fryxxse giri if f Patent Application Publication Dec. 13, 2012 Sheet 2 of 31 US 2012/0315630 A1 Optimize the Detecting Ab Dose Response Curve of Tryptase with Different Diilations of Detecting Aix AP-33 8 ::::::: & a 333 ::::::: :::: :::: : SY s s s s? & &s itxg frypt&e igri ris. Patent Application Publication Dec. 13, 2012 Sheet 3 of 31 US 2012/0315630 A1 Development of Sensitive Human Tryptase ELISA for the Detection of Tryptase in Human Serum Standard Curwe of Tryptase ESA :::::: :::::::: "", i.cg : y : asse giri ife, 3 Patent Application Publication Dec. 13, 2012 Sheet 4 of 31 US 2012/0315630 A1 lunar Tryptase Concentration in Serum from G Control (71), IESC (61), and BSD (203) Patients. Waites are expressed as near (SER). *p 8 (.0019 for BSD: Biarr writrey is test. t 3x e Patent Application Publication Dec. 13, 2012 Sheet 5 of 31 US 2012/0315630 A1 Tryptase Log Value Distribution leathy Control 8S Six i. s. Patent Application Publication Dec. 13, 2012 Sheet 6 of 31 US 2012/0315630 A1 Density Analysis for Tryptase Data ::8:333 x3:8:8 , is Patent Application Publication Dec. 13, 2012 Sheet 7 of 31 US 2012/0315630 A1 from healthy control Patent Application Publication Dec. 13, 2012 Sheet 8 of 31 US 2012/0315630 A1 Standard Curve of Human Tryptase 10000 ...'.xy..., x to ryptase is irri rf. 8 Patent Application Publication Dec. 13, 2012 Sheet 9 of 31 US 2012/0315630 A1 §§§§§§§§ {{{$ž §§§§§§§§* §§§§§§§8 §§§§§§§* $$$$$$$$$$$$ &: 3: Patent Application Publication Dec. 13, 2012 Sheet 10 of 31 US 2012/0315630 A1 & & s as X : F. ft. Patent Application Publication Dec. 13, 2012 Sheet 11 of 31 US 2012/0315630 A1 Patent Application Publication Dec. 13, 2012 Sheet 12 of 31 US 2012/0315630 A1 s s: - Patent Application Publication Dec. 13, 2012 Sheet 13 of 31 US 2012/0315630 A1 Syster rig. 3 Patent Application Publication Dec. 13, 2012 Sheet 14 of 31 US 2012/0315630 A1 g s 3. 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Patent Application Publication Dec. 13, 2012 Sheet 30 of 31 US 2012/0315630 A1 35. 3&{2se poleonunloaøiºanelog «!!!!!! sssssssss: if, Patent Application Publication Dec. 13, 2012 Sheet 31 of 31 US 2012/0315630 A1 ... if US 2012/03 15630 A1 Dec. 13, 2012 METHODS FOR DIAGNOSING RRITABLE visceral pain perception, known as peripheral sensitization. BOWEL, SYNDROME This sensitization involves a reduction in the threshold and an increase in the gain of the transduction processes of primary CROSS-REFERENCES TO RELATED afferent neurons, attributable to a variety of mediators includ APPLICATIONS ing monoamines (e.g., catecholamines and indoleamines), Substance P, and a variety of cytokines and prostanoids Such 0001. This application is a continuation of PCT/US2010/ as E-type prostaglandins (see, e.g., Mayer et al., Gastroen 054810 filed Oct. 29, 2010, which application claims priority terol., 107:271-293 (1994)). Also implicated in the etiopa to U.S. Provisional Application No. 61/256,717, filed Oct. 30, thology of IBS is intestinal motor dysfunction, which leads to 2009, U.S. Provisional Application No. 61/264,588, filed abnormal handling of intraluminal contents and/or gas (see, Nov. 25, 2009, and U.S. Provisional Application No. 61/326, e.g., Kellow et al., Gastroenterol., 92: 1885-1893 (1987); 176, filed Apr. 20, 2010, the disclosures of which are herein Levitt et al., Ann. Int. Med., 124:422-424 (1996)). Psycho incorporated by reference in their entireties for all purposes. logical factors may also contribute to IBS symptoms appear The following documents are also incorporated by reference: ing in conjunction with, if not triggered by, disturbances U.S. Patent Publication Nos. 2008/0085524, filed Aug. 14, including depression and anxiety (see, e.g., Drossman et al., 2007 and published Apr. 10, 2008; 2008/0166719, filed Aug. Gastroenterol. Int., 8:47-90 (1995)). 20, 2007, published Jul. 10, 2008. 0006. The causes of IBS are not well understood. The walls of the intestines are lined with layers of muscle that BACKGROUND OF THE INVENTION contract and relax as they move food from the stomach 0002 Irritable bowel syndrome (IBS) is the most common through the intestinal tract to the rectum. Normally, these of all gastrointestinal disorders, affecting 10-20% of the gen muscles contract and relax in a coordinated rhythm. In IBS eral population and accounting for more than 50% of all patients, these contractions are typically stronger and last patients with digestive complaints. However, studies suggest longer than normal. As a result, food is forced through the that only about 10% to 50% of those afflicted with IBS actu intestines more quickly in some cases causing gas, bloating, ally seek medical attention. Patients with IBS present with and diarrhea. In other cases, the opposite occurs: food pas disparate symptoms such as, for example, abdominal pain sage slows and stools become hard and dry causing constipa predominantly related to defecation, diarrhea, constipation or tion. alternating diarrhea and constipation, abdominal distention, 0007. The precise pathophysiology of IBS remains to be gas, and excessive mucus in the stool. More than 40% of IBS elucidated. While gut dysmotility and altered visceral percep patients have symptoms so severe that they have to take time tion are considered important contributors to symptom patho off from work, curtail their social life, avoid sexual inter genesis (Quigley, Scand. J. Gastroenterol. 38(Suppl. 237): course, cancel appointments, stop traveling, take medication, 1-8 (2003); Mayer et al., Gastroenterol., 122:2032-2048 and even stay confined to their house for fear of embarrass (2002)), this condition is now generally viewed as a disorder ment. The estimated health care cost of IBS in the United of the brain-gut axis. Recently, roles for enteric infection and States is S8 billion per year (Talley et al., Gastroenterol., intestinal inflammation have also been proposed. Studies 109:1736-1741 (1995)). have documented the onset of IBS following bacteriologi 0003 IBS patients are classified into three groups accord cally confirmed gastroenteritis, while others have provided ing to their predominant bowel symptoms: constipation-pre evidence of low-grade mucosal inflammation (Spiller et al., dominant IBS (IBS-C), diarrhea-predominant IBS (IBS-D) Gut, 47:804-811 (2000); Dunlop et al., Gastroenterol.
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