Expansion of stem/progenitor cells by inhibition of enzymatic reactions catalyzed by the Sir2 family of enzymes
Inventors
Assignees
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Publication Number
US-8986992-B2
Publication Date
2015-03-24
Expiration Date
Abstract
Provided are ex vivo and in vivo methods of expanding renewable stem cells using agents capable of down-regulating Sir2 protein activity and/or expression, expanded populations of renewable stem cells, and uses thereof.
Core Innovation
The invention provides a method of expanding and inhibiting differentiation of a population of hematopoietic stem cells or hematopoietic progenitor cells or both. The method includes providing the stem or progenitor cells or both with conditions for cell proliferation and expanding the stem or progenitor cells or both with an inhibitor of mammalian sirtuin deacetylase catalytic activity or expression.
The problem described is that cytokine-driven HSPC proliferation is coupled to differentiation. The invention addresses this coupling by inhibiting mammalian sirtuin deacetylase catalytic activity or expression, thereby uncoupling proliferation from differentiation in the expanded stem or progenitor cell population.
The inhibition is implemented using inhibitors of mammalian sirtuin deacetylase catalytic activity or expression, including Sir2 inhibitors. Examples referenced include nicotinamide, sirtinol, and splitomicin, and the description indicates that expanded cell populations are associated with increased primitive fractions and differentiation-less long-term expansion characteristics as described in the provided content.
Claims Coverage
The independent claim covers a two-part method that provides conditions for proliferation and uses an inhibitor of mammalian sirtuin deacetylase catalytic activity or expression to simultaneously expand hematopoietic stem/progenitor cells and inhibit differentiation. The provided dependent claim set further refines this coverage into ex vivo operation, inhibitor modality and examples, proliferation-condition selection, and enrichment for CD34+ cells.
Providing conditions for cell proliferation
Providing the stem or progenitor cells or both with conditions for cell proliferation.
Expanding with inhibitor of mammalian sirtuin deacetylase catalytic activity or expression
Expanding the stem or progenitor cells or both with an inhibitor of mammalian sirtuin deacetylase catalytic activity or expression.
Ex vivo expansion
Expanding and inhibiting differentiation of the population of stem or progenitor cells (or both) is carried out ex vivo.
Inhibitor selected among chemical inhibitor, peptide inhibitor, or neutralizing antibody
The inhibitor is selected from a chemical inhibitor, a peptide inhibitor, or a neutralizing antibody.
Chemical inhibitor of mammalian sirtuin deacetylase catalytic activity from specific examples
The inhibitor is a chemical inhibitor of mammalian sirtuin deacetylase catalytic activity selected from sirtinol, vitamin B3, M15, or splitomicin.
Proliferation conditions selected from differentiation chemical inhibitors, growth medium, and cytokines
The conditions for proliferation are selected from differentiation chemical inhibitors, a growth medium and cytokines.
Enrichment for CD34+ cells
The population of stem or progenitor cells (or both) is enriched for CD34+ cells.
Across the independent claim and provided dependent claim refinements, the core inventive coverage is the combination of proliferation-supporting conditions with an inhibitor of mammalian sirtuin deacetylase catalytic activity or expression to expand hematopoietic stem/progenitor cells while inhibiting differentiation, with additional constraints addressing ex vivo operation, inhibitor modality and examples, selected proliferation-condition components, and enrichment for CD34+ cells.
Stated Advantages
Expands a population of hematopoietic stem cells and/or hematopoietic progenitor cells while inhibiting differentiation.
Uncouples proliferation from differentiation in the expanded stem/progenitor population.
Documented Applications
Ex vivo expansion of hematopoietic stem/progenitor cells with inhibition of differentiation.
In vivo expansion of hematopoietic stem/progenitor cells.
Hematopoietic cell transplantation and adoptive immunotherapy.
Bone marrow mobilization and collection processes, including leukopheresis.
β-hemoglobinopathy and fetal hemoglobin induction.
Preservation/collection buffers.
In vivo differentiation/regen uses.
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