Engraftment of stem cells with a combination of an agent that targets stem cells and modulation of immunoregulatory signaling
The present invention provides a clinically applicable method of stem cell transplantation that facilitates engraftment and reconstitutes immunocompetence of the recipient without requiring radiotherapy or chemotherapy, and without development of GVHD or graft rejection. Aspects of the present invention are based on the discovery that the depletion of the endogenous stem cell niche facilitates efficient engraftment of stem cells into that niche. In particular, the present invention combines the use of selective ablation of endogenous stem cells with a combination of antibodies specific for CD117, and agents that modulate immunoregulatory signaling pathways, e.g. agonists of immune costimulatory molecules, in combination with the administration to the recipient of exogenous stem cells, resulting in efficient, long-term engraftment, even in immunocompetent recipients.
1. A method of treating a genetic blood disorder in a human patient, the method comprising:
genetically modifying a hematopoietic stem cell from the patient to correct a genetic defect for the genetic blood disorder; and
engrafting the genetically modified hematopoietic stem cells in the patient by:
contacting said patient concomitantly with (i) a monoclonal antibody specific for CD117 and (ii) an agent that blocks interaction between CD47 and SIRPα, wherein the agent is selected from an anti-CD47 antibody, an anti-SIRPα antibody, a soluble SIRPα polypeptide or a fusion protein comprising a SIRPα polypeptide; in a dose effective in ablating hematopoietic stem cells from bone marrow of said mammal; and
introducing the genetically modified hematopoietic stem cells to said patient, wherein the genetically modified hematopoietic stem cells engraft to provide treatment for the genetic blood disorder.
2. The method of claim 1 , wherein the genetic blood disorder is a hemoglobinopathy.
3. The method of claim 2 , wherein the hemoglobinopathy is sickle cell disease.
4. The method of claim 2 , wherein the hemoglobinopathy is a thalassemia.
5. The method of claim 1 , wherein the genetic blood disorder is aplastic anemia.
6. The method of claim 1 , wherein the genetic blood disorder is severe combined immunodeficiency (SCID).
7. The method according to claim 1 , wherein the engraftment is performed in the absence of myeloablative conditioning.
8. The method according to claim 1 , wherein the patient is immunocompetent.
9. The method according to claim 1 , wherein the agent that blocks interaction between CD47 and SIRPα comprises a soluble SIRPα polypeptide.
10. The method according to claim 1 , wherein the soluble SIRPα polypeptide is a high affinity SIRPα variant.
11. The method according to claim 1 , wherein the soluble SIRPα polypeptide is CV1.
12. The method according to claim 1 , wherein the agent is a fusion protein comprising a SIRPα polypeptide.
13. The method according to claim 12 , wherein the agent is a monomer or a dimer.
14. The method according to claim 1 wherein the agent that blocks interaction between CD47 and SIRPα is an anti-CD47 antibody.
15. The method according to claim 1 , wherein the agent that blocks interaction between CD47 and SIRPα is an anti-SIRPα antibody.
16. The method according to claim 1 , wherein said contacting is repeated at least twice.