Grant description

Bone marrow transplantation has been used for 60+ years to treat >1,000,000 patients suffering from many types of blood or immune diseases, and this therapy is the best current treatment for FA patients experiencing blood problems. This procedure relies on replacing sick blood-forming stem cells in patients with healthy ones from a donor, resulting in a completely new blood system. However, this currently requires use of irradiation and/or chemotherapy which can be extremely harmful, especially to FA patients whose cells cannot fix DNA mistakes caused by these agents. We think we can make this procedure safe and eliminate all of the bad side effects through use of antibodies that can target specific cells of the body, and together allow safe turnover of the bone marrow and eliminate bone marrow disease in FA patients. This type of therapy could not only be used to treat blood problems in FA patients, but also prevent them all together if used upfront in recently diagnosed patients.

Grant follow-up

The goal of this grant was to develop a non-genotoxic antibody-based conditioning regimen that can be used to treat people with FA who are undergoing a hematopoietic cell transplant (HCT). If successful, this new technology will ultimately eliminate the need for chemotherapy and irradiation during HCT. Results from this study showed that antibodies targeting the CD117 receptor on FA hematopoietic stem cells (HSCs) enables safe and effective HCT in FA mice when combined with T-cell depleting antibodies. Engraftment of donor cells in mouse models also showed that when specific immunosuppressant regimens are used donor HSCs have a competitive advantage over FA HSC cells. These studies open up the possibility of future immunosuppression-only HCTs for people with FA.

The Stanford team received a grant from the Department of Defense Bone Marrow Failure Research Program in September 2021 to continue their work on antibody-based conditioning in Fanconi anemia and initiated a clinical trial in 2022.