Compounds for inducing proliferation and differentiation of cells, and methods of use thereof

• US 10,081,609 B2
• Filed: 03/14/2014
• Issued: 09/25/2018
• Est. Priority Date: 03/15/2013
• Status: Active Grant

• Current Assignee: Massachusetts Institute of Technology, The Broad Institute, Inc.
• Original Assignee: Massachusetts Institute of Technology, The Broad Institute, Inc.
• Inventors: Bhatia, Sangeeta, Shan, Jing, Palmer, Michelle, Ross, Nathan
• Primary Examiner(s): Noble, Marcia Stephens
• Application Number:
  US14/772,284
• Publication Number:
  US 20160031837A1
• Time in Patent Office: 1,656 Days
• CPC Class Codes: A01K 2227/105 Murine
• CPC Class Codes: A01K 2267/0331 Animal model for proliferative diseases
• CPC Class Codes: A01K 67/0278 Knock-in vertebrates, e.g. humanised vertebrates
• CPC Class Codes: A61K 31/137 Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
• CPC Class Codes: A61K 31/403 condensed with carbocyclic rings, e.g. carbazole
• CPC Class Codes: A61K 31/4035 Isoindoles, e.g. phthalimide
• CPC Class Codes: A61K 31/4174 Arylalkylimidazoles, e.g. oxymetazolin, naphazoline, miconazole
• CPC Class Codes: A61K 31/4409 only substituted in position 4, e.g. isoniazid, iproniazid
• CPC Class Codes: A61K 35/12 Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells vaccines or medicinal preparations containing antigens or antibodies A61K39/00
• CPC Class Codes: A61K 35/407 Liver; Hepatocytes
• CPC Class Codes: C07C 211/32 containing dibenzocycloheptane or dibenzocycloheptene ring systems or condensed derivatives thereof
• CPC Class Codes: C07D 209/48 with oxygen atoms in positions 1 and 3, e.g. phthalimide
• CPC Class Codes: C07D 209/88 with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system
• CPC Class Codes: C07D 213/75 Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
• CPC Class Codes: C07D 263/24 with hydrocarbon radicals, substituted by oxygen atoms, attached to other ring carbon atoms
• CPC Class Codes: C12N 2501/02 Compounds of the arachidonic acid pathway, e.g. prostaglandins, leukotrienes
• CPC Class Codes: C12N 2501/115 Basic fibroblast growth factor (bFGF, FGF-2)
• CPC Class Codes: C12N 2501/12 Hepatocyte growth factor [HGF]
• CPC Class Codes: C12N 2501/155 Bone morphogenic proteins [BMP]; Osteogenins; Osteogenic factor; Bone inducing factor
• CPC Class Codes: C12N 2501/16 Activin; Inhibin; Mullerian inhibiting substance
• CPC Class Codes: C12N 2501/237 : Oncostatin M [OSM]
• CPC Class Codes: C12N 2501/999 : Small molecules not provided for elsewhere
• CPC Class Codes: C12N 2503/02 : Drug screening
• CPC Class Codes: C12N 2506/45 : from artificially induced pluripotent stem cells
• CPC Class Codes: C12N 2533/90 : Substrates of biological origin, e.g. extracellular matrix, decellularised tissue
• CPC Class Codes: C12N 5/06 : Animal cells or tissues; Human cells or tissues preservation of living cells or tissues A01N1/02
• CPC Class Codes: C12N 5/067 : Hepatocytes
• CPC Class Codes: Y02A 50/30 : Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The present invention provides methods of inducing proliferation of and/or differentiating cells comprising contacting cells with compounds within the methods of the invention. The present invention further provides cells obtainable by the methods of the invention. Liver disease affects more than 500 million people worldwide. Organ transplantation is the gold standard for treatment of liver failure, but organ shortages are acute.

Claims

1. A method of inducing differentiation of one or more induced pluripotent stem cell (iPS cell)-derived, immature hepatocyte cells (iHep cells), the method comprising:

contacting the one or more iHep cells with compound 105 (N,N′

-(methylenebis(4,1-phenylene))diacetamide);

or a pharmaceutically acceptable salt thereof;

wherein said contacting with the compound induces differentiation of the one or more immature iHep cells into mature hepatocytes.

2. The method of claim 1, wherein the mature hepatocytes derived from the one or more iHep cells contacted with compound 105 express elevated levels of albumin in culture.

3. The method of claim 1, wherein the mature hepatocytes derived from the one or more iHep cells contacted with compound 105 express minimal levels of alpha fetoprotein (AFP) in culture.

4. The method of claim 1, wherein the mature hepatocytes derived from the one or more iHep cells contacted with compound 105 express elevated levels of CYP34A and CYP2A6 activity in culture.

5. The method of claim 1, wherein the one or more iHep cells are human iHep cells.

6. The method of claim 1, wherein the one or more iHep cells is contacted with compound 105 ex vivo.

7. A method of inducing differentiation of one or more induced pluripotent stem cell (iPS cell)-derived endothelial cells, the method comprising contacting the one or more iPS cell-derived endothelial cells with compound 105 (N,N′

-(methylenebis(4,1-phenylene)) diacetamide), or a pharmaceutically acceptable salt thereof,

wherein said contacting with the compound induces differentiation of the one or more iPS cell-derived endothelial cells to produce a population of more mature nitric oxide-producing endothelial cells.

8. The method of claim 7, wherein the one or more iPS cell-derived endothelial cells is contacted with compound 105 ex vivo.