Granted Patent
B2
US 12,215,355 · App. 17/171,497 · Granted Feb 4, 2025
Stem cell derived islet differentiation
Assignee:
Vertex Pharmaceuticals Incorporated
C12N5/0678A61K35/39A61P5/50A61K2035/126C12N2500/46C12N2501/11C12N2501/117C12N2501/119C12N2501/15C12N2501/155C12N2501/16C12N2501/19C12N2501/415C12N2501/999
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Abstract
Provided herein are methods of producing β cells and precursors thereof utilizing a Wnt signaling inhibitor or PKC activator, or both. Also provided herein are in vitro cultures comprising said cells, methods of treating a subject with a disease characterized by high blood sugar levels over a prolonged period of time by administering said cells, and devices for encapsulating said cells.
Claims (20)
1. A composition comprising PDX1-positive, NKX6.1-positive pancreatic progenitor cells, a WNT signaling inhibitor, and one or more of a thyroid receptor signaling pathway activator, a protein kinase C activator, or a transforming growth factor (TGF)-β signaling pathway inhibitor, wherein the WNT signaling inhibitor is present at a concentration of 0.1 μM to 10 μM.
2. The composition of claim 1 , wherein said WNT signaling inhibitor comprises a tankyrase inhibitor that inhibits expression or activity of at least one tankyrase (TNKS) protein.
3. The composition of claim 2 , wherein said tankyrase signaling inhibitor is selected from the group consisting of: AZ 6102, JW55, 11N64, IWR-1-endo, TC-E5001, WIKI4, TNKS 22, TNKS 49, 2X-121 (E7449), XAV-939, G007-LK, NVP-TNKS656, decernotinib (VX-509), vismodegib (GDC-0449), IM-12, GSK429286A, INO-1001, Ofloxacin, TG101209, FG-4592, I-BET-762, LY2157299, MK-0752, Wnt-C59 (C59), MC1568, Pacritinib (SB1518), SB415286, Drocinostat, IWR-1-endo, Norfloxacin, SH-4-54, Nexturastat A, SB216763, UNC0.79, dephnetin, GF109203X, RepSox, Sotrastaurin, SB431542, tofacitinib (CP-690550), AG-14361, CI994 (tacedinaline), Ro 31-8220 mesylate, resveratrol, NVP-TNKS656, and YO-01027.
4. The composition of claim 1 , wherein said WNT signaling inhibitor comprises NVP-TNKS656.
5. The composition of claim 1 , wherein said WNT signaling inhibitor comprises XAV-939.
6. The composition of claim 1 , wherein said composition comprises about 1 μM to about 5 μM of said WNT signaling inhibitor.
7. The composition of claim 1 , wherein said composition comprises about 0.5 μM of said WNT signaling inhibitor.
8. The composition of claim 1 , further comprising PDX1-positive, NKX6.1-positive, ISL1-positive cells.
9. The composition of claim 1 , wherein said composition further comprises: a sonic hedgehog pathway inhibitor selected from the group consisting of: SANT1, SANT2, SANT4, Cur61414, forskolin, tomatidine, AY9944, triparanol, and cyclopamine.
10. The composition of claim 1 , wherein said composition further comprises a retinoic acid signaling pathway activator selected from the group consisting of: retinoic acid, CD1530, AM580, TTHRB, CD437, Ch55, BMS961, AC261066, AC55649, AM80, BMS753, tazarotene, adapalene, and CD2314.
11. The composition of claim 1 , wherein said composition further comprises a γ-secretase inhibitor comprising XXI or DAPT.
12. The composition of claim 1 , wherein said composition further comprises a growth factor from the epidermal growth factor family comprising betacellulin or EGF.
13. The composition of claim 1 , wherein said composition further comprises a bone morphogenetic protein signaling pathway inhibitor comprising LDN193189.
14. The composition of claim 1 , wherein said composition comprises said TGF-β signaling pathway inhibitor, and wherein said TGF-β signaling pathway inhibitor is selected from the group consisting of: Alk5i II, A83-01, SB431542, D4476, GW788388, LY364947, LY580276, SB505124, GW6604, SB-525334, and SD-208.
15. The composition of claim 1 , wherein said composition comprises said thyroid receptor signaling pathway activator, and wherein said thyroid receptor signaling pathway activator comprises T3 or GC-1.
16. The composition of claim 1 , wherein said composition further comprises a protein kinase inhibitor selected from the group consisting of: staurosporine, Ro-31-8220, a bisindolylmaleimide (Bis) compound, 10′-{5″-[(methoxycarbonyl) amino]-2″-methyl}-phenylaminocarbonylstaurosporine, a staralog, and cgp41251.
17. The composition of claim 1 , wherein said composition further comprises a ROCK inhibitor selected from the group consisting of Thiazovivin, Y-27632, and Fasudil/HA1077.
18. The composition of claim 1 , wherein said composition further comprises SANT1.
19. The composition of claim 1 , wherein said composition further comprises Alk5i II.
20. The composition of claim 1 , wherein said composition further comprises staurosporine.
Assignments (2)
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Feb 11, 2021
From: PAGLIUCA, FELICIA J.; HARB, GEORGE; YE, LILLIAN
To: SEMMA THERAPEUTICS, INC.
Reel/Frame 055224/0041 →
MERGER
Recorded Feb 11, 2021
From: SEMMA THERAPEUTICS, INC.
To: VERTEX PHARMACEUTICALS INCORPORATED
Reel/Frame 055224/0073 →
Continuity (3)
Continuation
PCTUS2019045985
· Aug 9, 2019
Provisional Application
62717665
· Aug 10, 2018
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