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EP-4735013-A1 - COMPOSITIONS COMPRISING ISOLATED ENDOTHELIAL PROGENITOR CELLS AND USES THEREOF

EP4735013A1EP 4735013 A1EP4735013 A1EP 4735013A1EP-4735013-A1

Abstract

The present technology comprises isolated endothelial progenitor cell (EPC) populations comprising PROCR+/- PDGFRA+/- EPCs and mesenchymal stem cell (MSC) populations, and methods of making and use thereof in treating hypoxic-ischemic encephalopathy (HIE) or brain injury in a subject.

Inventors

  • COLDITZ, Paul
  • KHOSROTEHRANI, Kiarash
  • KAUR, Simranpreet

Assignees

  • The University of Queensland

Dates

Publication Date
20260506
Application Date
20240628

Claims (20)

  1. 1. A pharmaceutical composition comprising or consisting of an isolated endothelial progenitor cell (EPC) population comprising PROCR+ PDGFRA+ EPCs.
  2. 2. A pharmaceutical composition comprising or consisting of an isolated EPC population comprising PROCR+/- PDGFRA+/- EPCs for use in treating neonatal hypoxic-ischemic encephalopathy (HIE) in a subject in need thereof.
  3. 3. A pharmaceutical composition comprising or consisting of an isolated EPC population comprising PROCR+/- PDGFRA+/- EPCs.
  4. 4. A pharmaceutical composition comprising or consisting of an isolated EPC population comprising PROCR+/- PDGFRA+/- EPCs for use in treating a brain injury in a subject in need thereof.
  5. 5. The pharmaceutical composition of claim 1 , wherein the isolated EPC population comprises an increase in a PROCR, a PDGFRA, or a VE-Cadherin protein expression level relative to an expression level in a non-isolated EPC population.
  6. 6. The pharmaceutical composition of claim 5, wherein the increase in the PROCR protein expression level is at least about 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, or 1000%, relative to a PROCR protein expression level in the non-isolated EPC.
  7. 7. The pharmaceutical composition of claim 5, wherein the increase in the PDGFRA protein expression level is at least about 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, or 1000%, relative to a PDGFRA protein expression level in the non-isolated EPC.
  8. 8. The pharmaceutical composition of any one of claims 1 -7, wherein the isolated EPC population comprises an increase in a PROCR, a PDGFRA, or a VE- Cadherin gene expression level relative to an expression level in a non-isolated EPC population.
  9. 9. The pharmaceutical composition of claim 8, wherein the increase in the PROCR gene expression level is at least about 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, or 1000%, relative to a PROCR gene expression level in the non-isolated EPC.
  10. 10. The pharmaceutical composition of claim 8, wherein the increase in the PDGFRA gene expression level is at least about 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, or 1000%, relative to a PDGFRA gene expression level in the non-isolated EPC.
  11. 11. The pharmaceutical composition of claim 8, wherein the increase in the VE-Cadherin gene expression level is at least about 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, or 1000%, relative to a VE-Cadherin gene expression level in the non-isolated EPC.
  12. 12. The pharmaceutical composition of any one of claims 1 -11 , wherein the isolated EPC population comprises an increased proliferative capacity relative to a nonisolated EPC population.
  13. 13. The pharmaceutical composition of any one of claims 1 -12, wherein the isolated EPC population comprises an increased angiogenic capacity relative to a nonisolated EPC population.
  14. 14. The pharmaceutical composition of claim 13, wherein the increase in the angiogenic capacity is at least about 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, or 1000%, relative to an angiogenic capacity level in the nonisolated EPC.
  15. 15. The pharmaceutical composition of any one of claims 1 -14, wherein the isolated EPC population comprises an increased in a colony forming capacity or a tube formation capacity relative to a non-isolated EPC population.
  16. 16. The pharmaceutical composition of claim 15, wherein the increase in the colony forming capacity is at least about 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, or 1000%, relative to a colony forming capacity level in the non-isolated EPC.
  17. 17. The pharmaceutical composition of claim 15, wherein the increase in the tube forming capacity is at least about 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, or 1000%, relative to a tube forming capacity level in the non-isolated EPC.
  18. 18. The pharmaceutical composition of any one of claims 1 -17, wherein the isolated EPC population comprises an increased engraftment potential relative to a nonisolated EPC population.
  19. 19. The pharmaceutical composition of claim 18, wherein the increase in the engraftment potential is at least about 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, or 1000%, relative to an engraftment potential level in the non-isolated EPC.
  20. 20. The pharmaceutical composition of any one of claims 1 -19, wherein the isolated EPC population comprises one or more EPCs having a more elongated cell shape, relative to one or more EPCs in a non-isolated EPC population.

Description

COMPOSITIONS COMPRISING ISOLATED ENDOTHELIAL PROGENITOR CELLS AND USES THEREOF BACKGROUND [0001] Vascularization is an essential process for both the growth of developing organs and the circulation of blood, whether in tissue maintenance or repair. Vasculogenesis and neovascularization both rely on a population of progenitor cells which self-renew, differentiate into mature endothelial cells, merging to form blood vessels de novo. As the endothelial layer is at continuous risk of defects, repair mechanisms may be permanently active via endothelial progenitor cells (EPCs). Numerous clinical trials using different cell types to promote vascular repair have been assesed. The most frequent sources utilized were early outgrowth EPCs from the peripheral circulation and bone marrow mononuclear cells (MNC). A major limitation in these early clinical studies relate to how EPCs were defined. Flow cytometry with CD34, VEGFR2 (KDR/FLK-1 ) and/or CD133 is conventionally used to identify the number of circulating endothelial progenitor cells, in addition to more classical endothelial markers such as vascular endothelial (VE)-cadherin or CD31 . However, the combination of CD34, VEGFR2, CD133, VE-cadherin and/or CD31 markers has not produced a reliable or discriminatory marker set. As such, there remains a need to provide more effective therapeutic treatments based on the use of EPCs, either alone, or in combination with other cell types. SUMMARY [0002] The present technology comprises pharmaceutical compositions comprising or consisting of isolated endothelial progenitor cell (EPC) populations, and methods of making and using the same. [0003] In some embodiments, the present technology comprises a pharmaceutical composition comprising or consisting of an isolated endothelial progenitor cell (EPC) population comprising PROCR+ PDGFRA+ EPCs. [0004] In some embodiments, the present technology comprises a pharmaceutical composition comprising or consisting of an isolated EPC population comprising PROCR+/- PDGFRA+/- EPCs for use in treating neonatal hypoxic-ischemic encephalopathy (HIE) in a subject in need thereof. [0005] In some embodiments, the present technology comprises a pharmaceutical composition comprising or consisting of an isolated EPC population comprising PROCR+/- PDGFRA+/- EPCs. [0006] In some embodiments, the present technology comprises a pharmaceutical composition comprising or consisting of an isolated EPC population comprising PROCR+/- PDGFRA+/- EPCs for use in treating a brain injury in a subject in need thereof. [0007] In some embodiments, the isolated EPC population comprises an increase in a PROCR, a PDGFRA, or a VE-Cadherin protein expression level relative to an expression level in a non-isolated EPC population. [0008] In some embodiments, the increase in the PDGFRA protein expression level is at least about 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, or 1000%, relative to a PDGFRA protein expression level in the nonisolated EPC. [0009] In some embodiments, the increase in the PROCR protein expression level is at least about 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, or 1000%, relative to a PROCR protein expression level in the non-isolated EPC. [0010] In some embodiments, the isolated EPC population comprises an increase in a PROCR, a PDGFRA, or a VE-Cadherin gene expression level relative to an expression level in a non-isolated EPC population. [0011] In some embodiments, the increase in the PROCR gene expression level is at least about 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, or 1000%, relative to a PROCR gene expression level in the non-isolated EPC. [0012] In some embodiments, the increase in the PDGFRA gene expression level is at least about 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, or 1000%, relative to a PDGFRA gene expression level in the non-isolated EPC. [0013] In some embodiments, the increase in the VE-Cadherin gene expression level is at least about 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, or 1000%, relative to a VE-Cadherin gene expression level in the nonisolated EPC. [0014] In some embodiments, the isolated EPC population comprises an increased proliferative capacity relative to a non-isolated EPC population. [0015] In some embodiments, the isolated EPC population comprises an increased angiogenic capacity relative to a non-isolated EPC population. [0016] In some embodiments, the increase in the angiogenic capacity is at least about 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 30