CXCR4 Reduction Leads to Enhancement of Engraftment of Hematopoietic Stem Cells

Methods of enhancing engraftment of donor hematopoietic stem cells (HSCs) by reducing expression or activity of CXCR4 in HSCs is described. HSC are the only cells in the bone marrow that are both pluripotent and long lived. Bone marrow transplantation (BMT) using HSC is an increasingly common medical therapy for severe hematologic cancers and primary hematologic immunodeficiencies. However, for significant HSC engraftment to occur there must usually be pre-transplant conditioning with either irradiation or chemotherapy or both. The technology described herein shows that it is possible to replace HSC without the need for pre-transplant conditioning regimen. It is known that the chemokine receptor CXCR4 plays a critical role in HSC homing to the bone marrow and in HSC quiescence. The inventors have identified a patient in which one copy of CXCR4 had been deleted in a somatic mutation of an HSC and this cell had clonally repopulated the bone marrow. This led to experiments in mice where the inventors clearly demonstrated in a bone marrow transplantation model, that donor cells with a single copy of the Cxcr4 gene repopulate recipient mice much faster and last much longer than donor cells having two copies of the Cxcr4 gene. This technology which shows that HSCs with one copy of the CXCR4 gene have a durable selective advantage in bone marrow repopulation can solve the problem frequently encountered in gene therapy, i.e., the short-lived nature of gene-corrected cells, by utilizing recently discovered gene editing methods that can be used to delete one copy of CXCR4 gene in gene-corrected cells.

Potential Commercial Applications: Competitive Advantages:
  • Improvement of engraftment in gene therapy protocols and in HSC transplantation.
  • Improved bone marrow transplantation, enhancing the efficiency and durability of donor cell repopulation.
  • This technology potentially facilitates HSC transplantation without the need of radiation or chemotherapy conditioning.
  • This technology may uniquely overcome a major hurdle limiting all gene therapy applications, namely the failure to correct the gene defect over a long time.

Development Stage:
  • Early-stage
  • In vitro data available
  • In vivo data available (animal)


Jiliang Gao (NIAID)  ➽ more inventions...

Philip Murphy (NIAID)  ➽ more inventions...

David Mcdermott (NIAID)  ➽ more inventions...

Marie Siwiki (NIAID)  ➽ more inventions...

Harry Malech (NIAID)  ➽ more inventions...

Qian Liu (NIAID)  ➽ more inventions...

Intellectual Property:
US Pat: - issued -
US Application No. 62/026,138 filed on 2014-07-18
PCT Application No. PCT/US2015/040954 filed on 2015-07-17

McDermott DH, et al. PMID 25662009

Licensing Contact:
Charles Rainwater,
Phone: 301-496-2644

OTT Reference No: E-173-2014-0
Updated: Jul 1, 2015