Methods of enhancing stem cell differentiation into beta cells
Inventors
Pagliuca, Felicia • Harb, George • Gurtler, Mads • THIEL, AUSTIN • YASIN, JIHAD • THOMPSON, EVRETT
Assignees
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Publication Number
US-12637661-B2
Publication Date
2026-05-26
Expiration Date
Abstract
Disclosed herein are compositions and methods of enhancing stem cell differentiation into beta cells with use of one or more epigenetic modification compounds. The present disclosure also relates to compositions and methods of sorting and enriching the differentiated beta cells. The present disclosure also relates to compositions and methods of irradiating cell population for reducing proliferation.
Core Innovation
The disclosure provides methods of treating a subject with Type 1 Diabetes by administering cell clusters comprising cells differentiated from pluripotent stem cells in vitro without fluorescent-protein-based flow-cytometric cell sorting. Staged differentiation and maturation utilize epigenetic modifiers, including histone deacetylase inhibitors and EZH2 or histone methyltransferase inhibitors, to increase chromogranin A-positive and C-peptide-positive populations while reducing off-target marker-expressing cells. The resulting cells proceed through definitive endoderm, gut-tube, pancreatic-progenitor, and endocrine intermediates, exhibiting glucose-stimulated insulin secretion.
The administered cell clusters exhibit defined marker proportions comprising at least 35% NKX6.1-positive and ISL1-positive cells, at most 3.2% double-negative cells, at least 60% CHGA-positive cells, and at least 30% C-peptide-positive cells. Treatment methods comprise administering autologous or HLA-compatible cell clusters, or co-administering cell clusters alongside an immune response modulator for reducing rejection of the cell clusters. In addition, treatments with bone morphogenetic protein, transforming growth factor-beta, and epigenetic modifiers provide improved cryopreservation recovery.
Claims Coverage
The claim coverage includes two independent claims directed to methods of treating a subject with Type 1 Diabetes using pluripotent-stem-cell-derived cell clusters, encompassing two inventive features.
Administration of specified autologous or HLA-compatible cell clusters
Claim 1 covers administering to a subject with Type 1 Diabetes a plurality of autologous or HLA-compatible cell clusters comprising cells differentiated from pluripotent stem cells in vitro. The clusters comprise at least 35% NKX6.1-positive and ISL1-positive cells, at most 3.2% NKX6.1-negative and ISL1-negative cells, at least 60% CHGA-positive cells, and at least 30% C-peptide-positive cells, wherein the cells are not subjected to cell sorting by flow cytometry based on a fluorescent protein expressed in the cells.
Administration of specified cell clusters with an immune response modulator
Claim 32 covers administering to a subject with Type 1 Diabetes pluripotent-stem-cell-derived cell clusters comprising at least 35% NKX6.1-positive and ISL1-positive cells, at most 3.2% NKX6.1-negative and ISL1-negative cells, at least 60% CHGA-positive cells, and at least 30% C-peptide-positive cells, without fluorescent-protein-based flow-cytometric sorting, in combination with an immune response modulator for reducing rejection of the cell clusters.
The independent claims cover treating Type 1 Diabetes using specified pluripotent-stem-cell-derived cell clusters without fluorescent-protein-based sorting, wherein one independent claim specifies autologous or HLA-compatible clusters and the other independent claim requires co-administration of an immune response modulator to reduce rejection.
Stated Advantages
Pre-thaw irradiation is reported to prolong glycemic control in implanted animal models.
The immune response modulator is administered for reducing rejection of the cell clusters.
Documented Applications
Treatment of Type 1 Diabetes by transplantation or administration of pluripotent-stem-cell-derived cell clusters, including autologous or HLA-compatible cell therapy.
Administration of an immune response modulator to reduce rejection of transplanted cell clusters.
Administration of cell clusters by intraportal infusion and use of an implantation-suitable device comprising a semipermeable membrane.
Transplantation of cell clusters in animal models to assess glycemia and post-transplant glucose control.
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