Stimulant for stem cell expansion in vivo to speed recovery of neutropenia secondary to chemotherapy and stem cell transplant

PROJECT SUMMARY Hematopoietic stem cell (HSC) transplants (HSCTs) are considered a potentially curative option for patients with certain cancers of the blood and bone marrow and over 20,000 HSCTs are performed in the US each year. However, HSCTs are associated with high risk due to the required removal of diseased bone marrow before transplantation. Until the transplanted cells engraft and proliferate enough to reconstitute the patient’s immune system, the patient is considered neutropenic during which they are highly susceptible to infection. In addition to the potentially life-threatening physical risk to the patient, neutropenia necessitates long hospitalization time that can in part drives the expensive cost of HSCTs ranging from $200,000-400,000 in the US depending on donor cell type. A current strategy in clinical trials is to transplant larger pools of donor HSCs to shorten the neutropenic phase. However, these approaches all rely on ex vivo culturing of donor cells that depend on imperfect man- made culture systems that may disrupt the proper function of the stem cells and can be prohibitively expensive. Ship of Theseus’ innovative solution is a drug that will be used for a brief, one-time exposure to donor cells prior to transplantation that improves expansion in vivo. Our drug is a patented mutant of Homeobox protein B4 (HOXB4(m)). HOXB4 is well-established to promote HSC expansion without altering differentiation. However, its progression to the clinic was stopped because the half-life of HOXB4 protein was too short to be practical for clinical use and genetically overexpressing HOXB4 resulted in myeloproliferative disorders. Our patented mutant has improved degradation resistance, elongating its intracellular half-life enough to be practical for clinical use while potentially avoiding adverse effects induced by constitutive overexpression. There is early preclinical data indicating treating cells with HOXB4(m) can expand all major lineages of HSCs while maintaining multipotency. The goal of this Phase I SBIR proposal is to perform proof-of-concept in vivo safety and efficacy of HOXB4(m). This will be accomplished through the execution of 2 aims. In Aim 1, we will demonstrate HOXB4(m)-treated cells can reduce the neutropenic phase compared to vehicle-treated after mouse-to-mouse HSCT in a short- term model. In Aim 2, we demonstrate long-term hematopoietic reconstitution without adverse effects or GVHD. We will perform HSCTs in mice with human HSCs treated with HOXB4(m) or vehicle in a long-term model. Successful completion of this Phase I program will demonstrate feasibility of HOXB4(m) as a drug for HSC expansion in vivo and provide the necessary data to support extensive in vivo efficacy and safety studies in a Phase II program necessary for an IND submission. With HOXB4(m), we can circumvent the original hurdles of HOXB4 and improve expansion in vivo to benefit HSCT patients by shortening the neutropenic phase to reduce infection, hospitalization time, and cost.PROJECT NARRATIVE Over 20,000 hematopoietic stem cell transplants are performed each year in the US and are used to treat certain cancers of the blood and bone marrow. Diseased bone marrow is removed and replaced with healthy cells, but patients are at high risk for infection and other life-threatening inflammatory conditions until the healthy cells expand enough to restart the immune system. Ship of Theseus has developed a therapeutic strategy to shorten this window of risk and improve patient outcomes by briefly treating donor cells with their novel drug, HOXB4(m), to increase the rate of expansion of hematopoietic stem cells in the patient without depending on cell expansion outside of the patient.