Engineering hematopoietic stem cells for chemotherapy-free gene therapy of monogenic blood disorders

• Applicant: Dr. Vasil Toskov
• Subject Area: Hematology, Oncology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 563172679

Currently, ex vivo hematopoietic stem cell (HSC) gene therapy (GT) requires (1) mobilization and collection of patient HSCs, (2) ex vivo gene editing, (3) myeloablative conditioning with chemotherapy, and (4) re-infusion and engraftment of edited HSCs. Even though the mobilization and collection methods have become efficient and safe, the toxic conditioning regimens are major limitations to scaling this approach to most patients with hematological disorders such as sickle cell disease. HSCs can be mobilized from patient bone marrow (BM) to peripheral blood (PB) by FDA- and EMA-approved drugs such as natalizumab. These block the interaction of receptors on HSCs with their ligands in the BM niche. Specifically, the integrin alpha 4ß1 (very late antigen 4, VLA-4) binds to vascular adhesion molecule-1 (VCAM1) to home and retain hematopoietic stem and progenitor cells (HSPCs) within the BM. The main hypothesis of the project is that the VLA-4 receptor may be engineered to no longer respond to its inhibitor but nonetheless retain ligand binding and receptor function. When administered to patients, these "mobilization-resistant" edited HSCs will selectively engraft the BM in presence of the mobilization-inducing drug. In contrast, unedited HSCs will vacate the BM. Thus, mobilization-resistant HSCs could obviate the need for myeloablative chemotherapeutic conditioning regimens typically required for hematopoietic engraftment.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Dr. Daniel E. Bauer, Ph.D.