Supported Research

TGF-β pathway inhibitors for the treatment of bone marrow failure in Fanconi anemia


Amount Funded: $175,000

Fanconi anemia (FA) patients suffer from progressive bone marrow failure due to the defective hematopoietic stem cells (HSCs) in their bone marrow. The mechanisms of why the HSCs in FA patients are defective remain elusive. Recent studies suggest that DNA damage induced by physiological stress or aldehydes in HSCs may contribute to the bone marrow failure in FA. Our laboratory has recently made an important discovery that hyperactive TGFbeta pathway signaling in FA bone marrow HSCs is the cause of bone marrow failure. We have recently published a paper describing this discovery (Zhang H et al, Cell Stem Cell, 2016). Specifically, we found that inhibition of the TGFbeta pathway by specific inhibitors improves the defects in HSCs from FA mice or FA patients by promoting DNA repair. Many of the inhibitors of TGFbeta pathway are currently under clinical trials. One such drug called Galunisertib is currently under clinical trial for Myelodysplastic syndrome (MDS) which is also a bone marrow disease. Our preliminary data suggest that Galunisertib significantly reduces DNA damage in HSCs from FA mice. We therefore plan to test Galunisertib and the other drugs related to Galunisertib for their ability to improve HSC defects in FA. In Specific Aim 1, we will test the drugs in in vitro tissue culture experiments using both mouse and human FA bone marrow cells. In Specific Aim 2, we will test the selected drug in preclinical FA mouse models.

Researchers: Alan D’Andrea