IP Library › Granted Patent US 12,285,464
Granted Patent B2
US 12,285,464 · App. 16/094,111 · Granted Apr 29, 2025

Therapeutic targets involved in the progression of nonalcoholic steatohepatitis (NASH)

Inventors: Ira Tabas (New City, NY); Xiaobo Wang (Fort Lee, NJ); Omid Farokhzad (Waban, MA); Xiaoding Xu (Malden, MA)
Assignees: The Trustees of Columbia University in the City of New York; The Brigham and Women's Hospital, Inc.
A61K38/17A61K9/1271A61K9/5073A61K31/4178A61K31/4439A61K31/7105A61K31/713A61K47/6929A61P1/16C12N15/113G01N33/50G01N33/6893A61K45/06C12N2310/14C12N2320/32
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Quick Facts
Patent No.
US 12,285,464
App. No.
16/094,111
Granted
Apr 29, 2025
Kind
B2
Abstract

The present invention relates to methods and compositions for specifically modulating the Hippo pathway transcription factor TAZ (WWTR1), as a therapeutic target for inhibiting or preventing liver conditions including the progression of steatosis-to-NASH in a patient.

Claims (7)

1. A method for treating or preventing progression of steatosis to non-alcoholic steatohepatitis (NASH) in a patient in need thereof, the method comprising administering to the patient in need thereof a therapeutically effective amount of an inhibitor of TAZ, where the inhibitor of TAZ is a nucleic acid comprising a sequence complementary to a sequence encoding human TAZ.

2. The method of claim 1 , wherein the inhibitor of TAZ is administered to at least one hepatocyte of said patient.

3. The method of claim 1 , further comprising administering a therapeutically effective amount of an inhibitor of Indian hedgehog (Ihh), an inhibitor of YAP, an inhibitor of TEAD1, and inhibitor of TEAD2, an inhibitor of TEAD3, an inhibitor of TEAD4, or any combination thereof.

4. The method of claim 1 , wherein the nucleic acid is selected from the group consisting of antisense oligonucleotide, siRNA, shRNA, and combinations thereof.

5. The method of claim 1 , wherein the sequence complementary to the sequence encoding human TAZ is set forth by SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NOs: 55-72, or SEQ ID NO: 81.

6. The method of claim 4 , wherein the nucleic acid is formulated in a nanoparticle.

7. The method of claim 6 , wherein the nanoparticle comprises: 1) a hydrophobic inner core, 2) a hydrophilic outer shell and 3) a hepatocyte targeting ligand.

Assignments (3)
CORRECTIVE ASSIGNMENT TO CORRECT THE THE SECOND INVENTORS NAME PREVIOUSLY RECORDED AT REEL: 052702 FRAME: 0618. ASSIGNOR(S) HEREBY CONFIRMS THE ASSIGNMENT. Recorded May 26, 2022
From: FAROKHZAD, OMID; XU, XIAODING
To: THE BRIGHAM AND WOMEN'S HOSPITAL, INC.
Reel/Frame 060199/0189 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 19, 2020
From: TABAS, IRA; WANG, XIAOBO
To: THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK
Reel/Frame 052702/0517 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 19, 2020
From: FAROKHZAD, OMID; XU, XIADING
To: THE BRIGHAM AND WOMEN'S HOSPITAL, INC.
Reel/Frame 052702/0618 →
Continuity (2)
Provisional Application 62323903 · Apr 18, 2016
Related Publication 20190255143A1 · Aug 22, 2019
References Cited (88)
US 20050019801A1 · Rubin et al. · 2005 [cited by applicant]
US 20060056948A1 · Hossain et al. · 2006 [cited by applicant]
US 20080050393A1 · Tang et al. · 2008 [cited by applicant]
US 20080081074A1 · Gu et al. · 2008 [cited by applicant]
US 20080193536A1 · Khademhosseini · 2008 [cited by applicant]
US 20090074828A1 · Alexis et al. · 2009 [cited by applicant]
US 20090298710A1 · Farokhzad · 2009 [cited by applicant]
US 20100022680A1 · Karnik et al. · 2010 [cited by applicant]
US 20100092425A1 · Von Andrian et al. · 2010 [cited by applicant]
US 20100129392A1 · Shi et al. · 2010 [cited by applicant]
US 20100129439A1 · Alexis et al. · 2010 [cited by applicant]
US 20100144845A1 · Farokhzad et al. · 2010 [cited by applicant]
US 20100183727A1 · Iannacone et al. · 2010 [cited by applicant]
US 20100196482A1 · Radovic-Moreno et al. · 2010 [cited by applicant]
US 20100203142A1 · Zhang et al. · 2010 [cited by applicant]
US 20100233251A1 · Von Andrian et al. · 2010 [cited by applicant]
US 20100303723A1 · Farokhzad et al. · 2010 [cited by applicant]
US 20100323199A1 · Gu et al. · 2010 [cited by applicant]
US 20110027172A1 · Wang et al. · 2011 [cited by applicant]
US 20110052697A1 · Farokhzad et al. · 2011 [cited by applicant]
US 20110065807A1 · Radovic-Moreno et al. · 2011 [cited by applicant]
US 20110092592A1 · Yano · 2011 [cited by applicant]
US 20110143993A1 · Langer et al. · 2011 [cited by applicant]
US 20110196187A1 · Ludwig et al. · 2011 [cited by applicant]
US 20110268804A1 · Shi et al. · 2011 [cited by applicant]
US 20110268805A1 · Alexis et al. · 2011 [cited by applicant]
US 20110300219A1 · Lippard · 2011 [cited by applicant]
US 20120087890A1 · Iannacone · 2012 [cited by applicant]
US 20120156135A1 · Farokhzad · 2012 [cited by applicant]
US 20120266491A1 · May · 2012 [cited by applicant]
US 20130017265A1 · Farokhzad et al. · 2013 [cited by applicant]
US 20130129790A1 · Alexis · 2013 [cited by applicant]
US 20130130348A1 · Gu et al. · 2013 [cited by applicant]
US 20130236533A1 · Von Andrian et al. · 2013 [cited by applicant]
US 20130287857A1 · Von Andrian et al. · 2013 [cited by applicant]
US 20130315831A1 · Shi · 2013 [cited by applicant]
US 20140017327A1 · Cheng et al. · 2014 [cited by applicant]
US 20140037736A1 · Shi et al. · 2014 [cited by applicant]
US 20140079776A1 · Lippard et al. · 2014 [cited by applicant]
US 20140127301A1 · Alexis et al. · 2014 [cited by applicant]
US 20140314864A1 · Cheng et al. · 2014 [cited by applicant]
US 20140314865A1 · Von Andrian et al. · 2014 [cited by applicant]
US 20150023875A1 · Farokhzad et al. · 2015 [cited by applicant]
US 20150125391A1 · Swami et al. · 2015 [cited by applicant]
US 20150157584A1 · Guan et al. · 2015 [cited by applicant]
US 20150157737A1 · Gu et al. · 2015 [cited by applicant]
US 20150174549A1 · Lim · 2015 [cited by applicant]
US 20150182461A1 · Kim et al. · 2015 [cited by applicant]
US 20150265716A1 · Valencia et al. · 2015 [cited by applicant]
US 20150342943A1 · Bornstein et al. · 2015 [cited by applicant]
US 20150377910A1 · McCreedy et al. · 2015 [cited by applicant]
US 20160008451A1 · Stary et al. · 2016 [cited by applicant]
US 20160017335A1 · Borodovsky et al. · 2016 [cited by applicant]
US 20160022835A1 · Farokhzad et al. · 2016 [cited by applicant]
US 20160187323A1 · Farokhzad et al. · 2016 [cited by applicant]
US 20160228574A1 · Farokhzad et al. · 2016 [cited by applicant]
US 20160338970A1 · Farokhzad et al. · 2016 [cited by applicant]
US 20160339113A1 · Von Andrian et al. · 2016 [cited by applicant]
WO 2014197738 · 2014 [cited by applicant]
WO 2015190760 · 2015 [cited by applicant]
WO 2015198077 · 2015 [cited by applicant]
Uno et al., Hepatology, 2008, 48: 109-118. [cited by examiner]
Wang et al , J. Control. Rel., 2013, 166: 106-114. [cited by examiner]
Black, Biochimie, 2007, 89: 1464-1473. [cited by examiner]
Breitkopf et al., Alcohol. Clin. Rxp. Res., 2005, 29: 121S-131S. [cited by examiner]
Miranda et al., FASEB J., Apr. 1, 2015, 29, 558.12; Abstract. [cited by examiner]
Hong et al., Science, 2005, 309: 1074-1078. [cited by examiner]
Cheng et al., Mol. Pharm., 2009, 6: 772-779. [cited by examiner]
Wang et al., Radiation Research. 2013, 179: 69-75. [cited by examiner]
Sequence alignment, 2021. [cited by examiner]
Inazaki, Kidney Int., 2004, 66: 597-604. [cited by examiner]
Wang, Lipids in Health and Disease, 2013, 12: 1-8. [cited by examiner]
Carmona-Cuenca, J. Hepatol., 2006, 49: 965-976. [cited by examiner]
International Search Report and Written Opinion dated Aug. 7, 2017 corresponding to International Patent Application No. PCT/US2017/028109; 2 pages. [cited by applicant]
Bertero et al. “A YAP/TAZ-miR-130/301 molecular circuit exerts systems-level control of fibrosis in a network of human diseases and physiologic conditions,” Scientific Reports, Dec. 15, 2015 (Dec. 15, 2015), vol. 5, pp.… [cited by applicant]
Sanyal et al., Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med. May 6, 2010;362(18):1675-85. [cited by applicant]
Paul Angulo. Nonalcoholic Fatty Liver Disease. N Engl J Med 2002; 346:1221-1231. [cited by applicant]
Angulo et al., Fibrosis in nonalcoholic Fatty liver disease: mechanisms and clinical implications, Semin Liver Dis. 2015;35(2):132-45. [cited by applicant]
Fitzgerald et al. “A Highly Durable RNAi Therapeutic Inhibitor of PCSK9”, N. Engl. J. Med. 2017; 376:41-51. [cited by applicant]
Anastasia Khvorova, Oligonucleotide Therapeutics—A New Class of Cholesterol-Lowering Drugs, N Engl J Med. 2017; 376(1):4-7. [cited by applicant]
Zuckerman et al.,“Clinical experiences with systemically administered siRNA-based therapeutics in cancer”, Nat. Rev. Drug Discov. 2015;14(12):843-56. [cited by applicant]
Lutz et al., Cooperative function of YAP and TAZ in hepatocytes and hepatocarcinogenesis, Zeitschrift Fur Gastroenterologie, 2015, vol. 53, No. 1, pp. A4-A10. [cited by applicant]
Machado et al, Accumulation of duct cells with activated YAP parallels fibrosis progression in non-alcoholic fatty liver disease, Journal of Hepatology, 2015, vol. 63, No. 4, pp. 962-970. [cited by applicant]
Johnson et al, The two faces of Hippo: Targeting the Hippo pathway for regenerative medicine and cancer treatment, Nature Reviews. Drug Discovery, 2014, vol. 13, No. 1, pp. 63-79. [cited by applicant]
Wang et al, Hepatocyte TAZ/WWTRI Promotes Inflammation and Fibrosis in Nonalcoholic Steatohepatitis, Cell Metabolism, 2016, vol. 24, No. 6, pp. 848-862. [cited by applicant]
Supplementary European Search Report dated Oct. 23, 2019 in European Patent Application EP 17786458. [cited by applicant]
Day et al: “Steatohepatitis: A tale of two “hits” ? ”, Gastroenterology, vol. 114, No. 4, 1998, pp. 842-845. [cited by applicant]
Hideki Fujii et al: “Inflammation and fibrogenesis in steatohepatitis”, Journal of Gastroenterology, vol. 47, No. 3, 2012, pp. 215-225. [cited by applicant]