Expansion of stem/progenitor cells by inhibition of enzymatic reactions catalyzed by the Sir2 family of enzymes

Inventors

Peled, Tony

Assignees

Gamida Cell Ltd

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 patent describes a method of expanding and inhibiting differentiation of a population of hematopoietic stem cells and/or hematopoietic progenitor cells. The method provides the stem and/or progenitor cells ex vivo with conditions for cell proliferation and then ex vivo expands the cells while inhibiting differentiation. The differentiation inhibition is achieved by using an inhibitor of mammalian sirtuin deacetylase catalytic activity, selected from sirtinol, M15, and splitomicin.

The background premise links the differentiation process to mammalian sirtuin activity, describing sirtuin as a class III NAD+-dependent deacetylase. The patent characterizes sirtuin catalytic activity as an NAD+-dependent deacetylation reaction that produces OAADPr and ADP-ribose metabolites. Based on this, the patent rationalizes targeting Sir2/Sirtuin catalytic activity rather than HDAC, to inhibit differentiation while supporting expansion.

The patent states a need for differentiation-less expansion of hematopoietic stem/progenitor cells for uses including transplantation and other therapies. It further positions transient inhibition of differentiation to enable therapeutic induction of fetal hemoglobin, and connects expanded undifferentiated cells to downstream uses such as transduction with exogenous material and adoptive immunotherapy. The provided summary includes experimental support indicating that inhibitors such as nicotineamide and splitomicin can enhance expansion while preserving early progenitor phenotypes and colony-forming potential.

Claims Coverage

The provided claim set includes one independent method claim. The inventive features in this independent claim cover ex vivo proliferation conditions together with an inhibitor of mammalian sirtuin deacetylase catalytic activity to expand hematopoietic stem cells and/or hematopoietic progenitor cells while inhibiting differentiation, using an inhibitor selected from sirtinol, M15, and splitomicin.

Across the independent claim, the patent’s claim coverage is focused on combining ex vivo proliferation and expansion of hematopoietic stem/progenitor cells with differentiation inhibition through inhibition of mammalian sirtuin deacetylase catalytic activity, using sirtinol, M15, or splitomicin.

Stated Advantages

Documented Applications