A Novel Bone Marrow Transplantation Approach for Sickle Cell Disease Using Targeted Marrow Irradiation

PROJECT SUMMARY Sickle Cell Disease (SCD) is the most common hematologic disorder affecting millions of people worldwide. Allogeneic hematopoietic cell transplantation (HCT) is the only curative treatment but is associated with a significant risk of treatment-related organ toxicities and graft failure. While myeloablative total body irradiation (TBI) conditioning facilitates full engraftment, it is associated with higher organ toxicities. Conversely, reduced intensity conditioning is associated with less organ toxicities, but the risk of graft rejection is higher, and partial chimerism achieved with RIC cannot resolve the hematological abnormalities in most cases. Therefore, a conditioning regimen that can increase chimerism while lowering regimen-related toxicities is an unmet need to treat SCD. We recently successfully treated our first SCD patient with image-guided total marrow irradiation (TMI), delivering 6 Gy of radiation to the bone marrow (BM) while limiting the vital organ dose to 0-2 Gy, followed by matched donor HCT, which resulted in full chimerism without adverse events. Yet, the exact mechanism of the enhanced donor chimerism after TMI is not clear; emphasizing the need for preclinical studies. We have developed the first preclinical 3D image-guided TMI bone marrow transplant (BMT) model, using immunocompetent C57BL/6 mice and humanized homozygous BERK sickle mice (SS). Initial work suggests TMI-based bone marrow targeted dose escalation is feasible in the SCD mice model supporting increased chimerism and reduced organ damage. In collaboration with Janssen Pharmaceuticals, we will test a thrombopoietin (TPO) mimetic drug (TPOm, aka JNJ-26366821), which is a fully synthetic, PEGylated TPO receptor, c-MPL agonist peptide. The safety of TPOm has been proven in Phase I clinical trials and is phase II ready. Our preliminary data in a mouse model suggest post-BMT TPOm administration can enhance HSC regeneration, mitigate radiation damage, and support vascular regeneration. We hypothesize that the TMI- based dose escalation will facilitate engraftment (higher homing and chimerism) with minimal toxicities to other organs, resulting in improved pathophysiology of SCD. We further hypothesize that TPOm intervention along with TMI will improve BM vascular recovery, HSC expansion, and engraftment. To test the hypothesis, we will Optimize donor cell homing, engraftment, and expansion after BMT in a rodent SCD model using the following sub-aims. We will identify the optimal TMI dose to enhance donor chimerism and full engraftment which will reduce hemolysis, anemia, and tissue damage. We will investigate how TMI-based differential dose escalation activates SDF-1 gradient to support increasing donor cell homing to the bone marrow. Investigate if adding TPOm can further improve engraftment by augmenting BM vascular recovery and donor HSC expansion. The overarching goal of our interdisciplinary proposal is to produce a clinically relevant, effective, and safe TMI dose escalation alone or in combination with TPOm to improve chimerism and vascular regeneration while lowering regimen-related toxicities after HCT for SCD.