Islet cell manufacturing compositions and methods of use
Inventors
THIEL, AUSTIN • YASIN, JIHAD • THOMPSON, EVRETT • Pagliuca, Felicia J.
Assignees
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Publication Number
US-12304900-B2
Publication Date
2025-05-20
Expiration Date
Abstract
Disclosed herein are compositions and methods useful for manufacturing SC-β cell, and isolated populations of SC-β cells for use in various applications, such as cell therapy.
Core Innovation
A composition is provided that includes a population of PDX1-negative primitive gut tube cells and a BMP signaling pathway inhibitor, where the inhibitor is a compound of Formula A. The disclosure emphasizes using BMP signaling pathway inhibition together with TGF-β superfamily growth factors, including Activin A, to direct stem cell differentiation toward pancreatic progenitor and β-like cell outcomes while managing marker profiles associated with off-target differentiation.
The patent describes a differentiation scheme proceeding from Pdx1+ pancreatic lineage cells to NKX6.1+ progenitors, to insulin+ endocrine cells, and to SC-β cells. It further identifies pathway modulation components including SHH signaling pathway inhibitors, retinoic acid signaling pathway activators, ROCK inhibitors, TGF-β superfamily activators, TGF-β signaling pathway inhibitors, γ-secretase inhibitors, thyroid hormone signaling pathway activators, EGF family factors, and PKC inhibitors.
The document further describes scalable xeno-free and serum-free culture conditions and downstream uses for the generated stem cell-derived β cells (SC-β). It also includes pharmaceutical compositions, devices that use non-native β cells or SC-β cells, cryopreservation, and treatment-by-implantation concepts, including implantable insulin-releasing devices that use a semipermeable membrane or an alginate microcapsule.
Claims Coverage
The independent claim is directed to a composition combining PDX1-negative primitive gut tube cells with a BMP signaling pathway inhibitor defined as a compound of Formula A. Dependent claims add specific TGF-β superfamily growth factor selections, quantitative concentration ranges, and component-set cardinality constraints.
PDX1-negative primitive gut tube cells with formula a BMP inhibitor
A composition comprising a population of PDX1-negative primitive gut tube cells and a BMP signaling pathway inhibitor, wherein the BMP signaling pathway inhibitor is a compound of Formula A.
Bmp inhibitor concentration range
The composition includes about 0.1 μM to about 0.3 μM of a BMP signaling inhibitor.
Activin a concentration range
The composition includes Activin A at a concentration of about 2 ng/ml to about 50 ng/ml.
TGF-β superfamily growth factor selection set
The composition includes a growth factor from the TGF-β superfamily chosen from a specified list including inhibin, activin, Mullerian inhibiting substance (MIS), BMP, dpp, Vg-1, monoclonal nonspecific suppressor factor (MNSF), GDF8, and GDF11.
Defined set cardinality constraint
The composition includes two or more specified components selected from KGF, SANT1, retinoic acid, PdbU, and thiazovivin.
Addition of pdbu
The composition further includes PdbU in addition to the composition of the preceding claim.
Overall, the claims focus on a composition defined by PDX1-negative primitive gut tube cells combined with a Formula A BMP signaling pathway inhibitor, with dependent claims narrowing the formulation through specified concentration ranges and selected component sets, including TGF-β superfamily growth factors and additional factors such as KGF, SANT1, retinoic acid, PdbU, and thiazovivin.
Stated Advantages
Improved glucose-stimulated insulin secretion (GSIS) stimulation index and fold-increases.
Reduced off-target marker expression, including CHGA and CDX2.
Defined marker-positive percentage outcomes by flow cytometry, including Pdx1/NKX6.1 stage-associated characterization.
Scalable xeno-free culture conditions.
Supports downstream uses including cell therapy, pharmaceutical compositions, and implantable insulin-releasing devices.
Increased SC-β percentages.
Improved GSIS.
Cryopreservation and diabetes treatment in animal models.
Documented Applications
Cell therapy using the generated stem cell-derived β cells (SC-β).
Pharmaceutical compositions containing the generated stem cell-derived β cells.
Implantable insulin-releasing devices, including configurations using a semipermeable membrane or an alginate microcapsule.
Diabetes treatment, including diabetes treatment in animal models, using non-native β cells or SC-β cells and treatment-by-implantation concepts.
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