LIVER ORGANOID COMPOSITIONS AND METHODS OF MAKING AND USING SAME
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IPC분류정보
국가/구분
United States(US) Patent
공개
국제특허분류(IPC7판)
A61K-035/407
C12N-005/074
C12N-005/071
A61P-001/16
출원번호
16346188
(2017-11-03)
공개번호
20190298775
(2019-10-03)
국제출원번호
PCT/US17/59845
(2017-11-03)
발명자
/ 주소
Takebe, Takanori
Shinozawa, Tadahiro
Koike, Hiroyuki
Kimura, Masaki
출원인 / 주소
Takebe, Takanori
인용정보
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0인용 특허 :
0
초록▼
Disclosed are methods of inducing formation of a liver organoid from precursor cells, such as iPSC cells. The disclosed liver organoids may be used for screening for a serious adverse event (SAE), such as liver failure and/or drug induced liver injury (DILL), and/or drug toxicity. The disclosed live
Disclosed are methods of inducing formation of a liver organoid from precursor cells, such as iPSC cells. The disclosed liver organoids may be used for screening for a serious adverse event (SAE), such as liver failure and/or drug induced liver injury (DILL), and/or drug toxicity. The disclosed liver organoids may also be used to treat an individual having liver damage, or for identifying a preferred therapeutic agent.
대표청구항▼
1. A method of inducing formation of a liver organoid from iPSC cells, comprising the steps of a) contacting definitive endoderm (DE) derived from said iPSC cells with a FGF pathway activator and a GSK3 inhibitor, for a period of time sufficient to form posterior foregut spheroids;b) incubating said
1. A method of inducing formation of a liver organoid from iPSC cells, comprising the steps of a) contacting definitive endoderm (DE) derived from said iPSC cells with a FGF pathway activator and a GSK3 inhibitor, for a period of time sufficient to form posterior foregut spheroids;b) incubating said posterior foregut spheroids of step a in the presence of retinoic acid (RA) for a period of time sufficient to form said liver organoid. 2. The method of claim 1, wherein said stem cells are human iPSCs. 3. The method of claim 1, wherein said foregut spheroids are embedded in a basement membrane matrix. 4. The method of claim 1, wherein said HLOs are characterized by expression of alpha-fetoprotein (AFP), albumin (ALB), retinol binding protein (RBP4), cytokeratin 19 (CK19), hepatocyte nuclear factor 6 (HNF6), and cytochrome P450 3A4 (CYP3A4), HNF4a, E-cadherin, DAPI, and Epcam. 5. The method of claim 1, wherein said HLOs have bile transport activity. 6. A liver organoid derived from a stem cell, wherein said liver organoid comprises a luminal structure comprising internalized microvilli comprising mesenchymal cells; and wherein said luminal structure is surrounded by polarized hepatocytes. 7. The liver organoid of claim 6 wherein said stem cell is a human iPSC. 8. The liver organoid of claim 6 wherein said liver organoid comprises functional stellate cells and functional Kupffer cells. 9. The liver organoid of claim 6 wherein said liver organoid is characterized by having one or more characteristics selected from bile production capacity, bile transport activity, Complement factor H expression of at least 50 ng/mL/1×e6 cells/24 hr, Complement factor B of at least 40 ng/mL/1×e6 cells/24 hr, C3 expression of at least 1000 ng/mL/1×e6 cells/24 hr; C4 expression of at least 1000 ng/mL/1×e6 cells/24 hr, fibrinogen production of at least 1,000 ng/mL/1×e6 cells/24 hr and albumin production of at least 1,000 ng/mL/1×e6 cells/24 hr. 10. (canceled) 11. The liver organoid of claim 6, wherein said liver organoid expresses one or more genes selected from PROX1, RBP4, CYP2C9, CYP3A4, ABCC11, CFH, C3, C5, ALB, FBG, MRP2, ALCAM, CD68, CD34, CD31. 12. The liver organoid of claim 6, wherein said HLO comprises a drug metabolism cytochrome variant. 13. The liver organoid of claim 6, wherein said liver organoid does not comprise inflammatory cells. 14. (canceled) 15. (canceled) 16. (canceled) 17. (canceled) 18. A method of treating an individual having liver damage, comprising implanting a liver organoid into said individual. 19. The method of claim 18, wherein said liver damage is selected from metabolic liver disease, end stage liver disease, or a combination thereof. 20. A method of identifying a preferred therapeutic agent for an individual, comprising contacting a liver organoid derived from an iPSC of interest with a candidate compound. 21. (canceled) 22. (canceled) 23. (canceled)
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