GABA agonists and antagonists affect differentiation of hematopoietic stem cells and megakaryocyte progenitors
Inventors
ZHU, FANGFANG • Weissman, Irving L.
Assignees
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Publication Number
US-12589114-B2
Publication Date
2026-03-31
Expiration Date
Abstract
GABRR1 is shown to be expressed on subsets of hematopoietic stem cells (HSCs) and megakaryocyte progenitors (MkPs). Inhibition of GABRR1 inhibits MkP differentiation and reduction of platelet numbers in blood. Overexpression of GABRR1 or treatment with agonists significantly promotes MkP generation and growth of megakaryocytes.
Core Innovation
The invention relates to using γ-aminobutyric acid rho receptor 1 (GABRR1) to modulate hematopoiesis toward a megakaryocytic lineage. GABRR1 is described as being expressed on subsets of hematopoietic stem cells (HSCs) and megakaryocyte progenitors (MkPs), and it is described as functional in this cellular context.
In the described systems, inhibiting GABRR1 activity reduces megakaryocyte progenitor differentiation and reduces platelet numbers, including via GABRR1 inhibition by genetic knockout and/or antagonist SR95531. Conversely, increasing GABRR1 signaling is described as promoting megakaryocyte progenitor generation and megakaryocyte colony output, including with GABRR1 overexpression and agonists such as γ-aminobutyric acid (GABA), TACA, and muscimol.
The document further describes that GABRR1 is mainly present on HSC/multipotent progenitor (HSC/MPP), common myeloid progenitors (CMP), and MkP populations, and that modulating GABRR1 alters megakaryocyte versus erythroid progenitor (EP) frequencies. Corresponding changes in megakaryocytic gene expression and CFU-MK colony output are described alongside the lineage composition changes.
Claims Coverage
The partial content includes two independent claims. Each independent claim centers on increasing the megakaryocytic lineage by activating GABRR1, one in vitro to increase megakaryocytic lineage cells, and the other in vivo to increase platelet levels, with measurement-based confirmation relative to a control condition.
In vitro GABRR1 agonist increases megakaryocytic lineage production
Contacting CD34+ hematopoietic stem or progenitor cells in culture with an effective dose of a γ-aminobutyric acid rho receptor (GABRR) agonist wherein the GABRR receptor is GABRR1, selecting CD34+ hematopoietic stem or progenitor cells that are one or more of hematopoietic stem cells (HSC), multipotent progenitors (MPP), common myeloid progenitors (CMP) and megakaryocyte erythroid progenitors (MEP), measuring for the presence of megakaryocytic lineage cells selected from megakaryocyte progenitor cells (MkP), megakaryocytes and platelets, wherein production of megakaryocytic lineage cells in the culture is increased relative to culture in the absence of the GABRR1 agonist.
In vivo GABRR1 agonist increases platelet levels by measuring megakaryocytic lineage
Administering in vivo to the mammalian subject a γ-aminobutyric acid rho receptor 1 (GABRR1) agonist in a dose effective to increase platelet levels in the subject; and measuring an increase in megakaryocytic lineage cells selected from megakaryocyte progenitor cells, megakaryocytes and platelets, wherein platelet levels are increased relative to an untreated control.
Across both independent claims, the coverage focuses on GABRR1 activation as the key enabling concept: (i) an in vitro contact method with a GABRR1 agonist that increases megakaryocytic lineage cell production relative to absence of the agonist, and (ii) an in vivo administration method of a GABRR1 agonist that increases platelet levels relative to an untreated control, with measurement of megakaryocytic lineage cell increases.
Stated Advantages
Increasing production of megakaryocytic lineage cells (MkP, megakaryocytes, and platelets) in culture relative to culture without the GABRR1 agonist.
Increasing platelet levels in a mammalian subject, with platelet levels increased relative to an untreated control.
Documented Applications
In vitro production of megakaryocytic lineage cells from CD34+ hematopoietic stem or progenitor cells by culturing with a GABRR1 agonist.
In vivo increase of platelet levels in a mammalian subject by administering a GABRR1 agonist, with measurement of increases in megakaryocytic lineage cells relative to an untreated control.
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