Mobilization of hematopoietic cells

Patent Number: 7,417,026

Mobilization of stem cells is a very hot area these days.  At face value, mobilization is important for donors of hematopoietic stem cells since it alleviates the need for performing puncture of the iliac crest of healthy people who are donating bone marrow.  Currently, mobilization is performed by administering to the donor G-CSF (neupogen), which activates a cascade of enzymes and complement and releases hematopoietic stem cells from their bone marrow niche into peripheral circulation.  This allows for hematopoietic stem cells to be collected from the peripheral blood. 

Another reason why mobilization is important is for autologous hematopoietic stem cell transplants.  In patients with various cancers it is possible to induce the stem cells to enter circulation, purify or "purge" tumor cells out of the mobilized stem cells, give the patient a high dose of chemo and/or radiation, and then put back the patient's own hematopoietic stem cells.  However some patients do not mobilize properly.  This is why people are always looking for new agents that can mobilize stem cells, especially in patients that do not respond to G-CSF.   The need for agents that mobilize stem cells is so big that last year Genzyme paid almost half a billion dollars for the company Anormed which is developing a CXCR-4 antagonist that mobilizes stem cells.

In situations of tissue injury, such as stroke or heart attack, endogenous stem cells are mobilized to leave the bone marrow and enter systemic circulation.  Mobilization of the stem cells by injury does not appear to be an inconsequential event.  In patients with stroke, the larger the extent of stem cell mobilization, the better outcome the patients have.  Therefore, one of the areas of use for stem cell mobilizers is to increase the extent of mobilization post tissue injury in order to accelerate regeneration.

Numerous agents have previously been demonstrated to mobilize stem cells, ranging from toll like receptor agonists, to beta glucan, to parathyroid hormone.  In the current patent, a new way of mobilizing hematopoietic stem cells is revealed.

 In the broadest claim the patent covers:

"A method for mobilizing peripheral blood precursor cells from bone marrow into peripheral blood comprising: administering to a subject in need of treatment to mobilize peripheral blood precursor cells, an effective amount of at least one GTPase inhibitor"

Dependent claims include inhibitors of rac1 and rac2, as well as specific peptide sequences capable of inhibiting GTPases. 

The rac family of GTPases is involved in cytoskeletal rearrangement, so maybe interference at this level is associated with physical changes in the bone marrow hematopoietic stem cell shape or migratory activity.  The specification provides examples of mobilization using small molecule Rac inhibitors, as well as data from Rac knockout mice showing deficiencies in mobilization.

View this patent on the USPTO website.