Testing senescence-targeting therapies to improve hematopoietic stem cell function and mobilization during sickle cell disease

About This Grant

Project Summary Sickle cell disease (SCD) is an inherited hemolytic anemia that afflicts 100,000 patients in the United States and millions worldwide. Those with SCD suffer from recurrent pain, ischemia-perfusion injury, chronic inflammation, progressive organ damage and a shortened life and healthspan. SCD epitomizes chronic hematologic stress in the form of bone marrow (BM) inflammation, increased hematopoietic demand, and BM niche damage, which can damage and deplete BM hematopoietic stem and progenitor cells (HSPCs). Evidence is building that the pathologic stress of SCD selects for mutant HSPCs that put patients at risk for additional hematologic disease, especially when subject to stressors such as exposure to cytotoxic chemotherapy prior to hematopoietic cell transplant (HCT) or during gene therapy. As these are the only potentially curative therapies for SCD, it is important to better understand and prevent SCD-induced insults to HSPCs. We found that BM HSPCs from mice and SCD individuals contain DNA damage, oxidative stress, and precocious senescence. These phenotypes correlated with a severe loss of blood repopulating and hematopoietic colony activity from the BM of mice and individuals with SCD, respectively, that inversely correlated with high expression of molecular enforcers of senescence. We demonstrated that treatment of SCD mice with the senescence targeting therapy (STT), navitoclax (ABT-263), reduced numbers of HSPCs with DNA damage and restored hematopoietic repopulating activity to the BM. Thus, STTs have the potential to rejuvenate damaged BM HSPCs for downstream applications in hematopoietic cell transplant and gene therapy in SCD. Here, we propose to build on these promising ‘proof of principle’ studies and establish the pre-clinical rationale for STTs to improve HSPC function and numbers during SCD. As navitoclax causes dose-limiting cytopenias and is not FDA approved, in Aim 1 we will employ a pre-clinical SCD mouse model and BM HSPCs from individuals with SCD to interrogate the ability of FDA-approved STTs to restore function to BM HSPCs during SCD. We will also define the therapeutic window of STTs in our pre-clinical SCD model. In Aim 2, we will test our hypothesis that STTs can improve the mobilization of high-quality HSPCs during SCD following treatment with the CXCR4 antagonist, plerixafor, using a pre-clinical model of SCD. We will also test mobilized cells for gene editing efficiency in furtherance of translating this work to our ongoing clinical trial for gene editing-based autologous therapy for SCD (SAGES1, NCT06506461). In Aim 3, we will interrogate the cellular mechanisms behind improved function following STT during SCD and test the hypothesis that non-cell autonomous effects on BM HSPCs contribute to their restored function. Via this work, we will establish the pre-clinical rationale for STTs as a tool to improve the function of HSPCs in individuals with SCD, which has major implications for the emerging field of potentially curative therapies for SCD.