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Researchers aim to better define development of Fanconi anemia in children
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Researchers at West Virginia University have found that p53-TIGAR-mediated glycolytic suppression decreases DNA damage, improves chromosomal instability and consequently prevents premature exhaustion in Fanconi anemia hematopoietic stem cells.
This discovery could lead to new and more effective treatments for Fanconi anemia, an incurable blood disease typically diagnosed in children.
“Our findings reveal a novel function of the p53TIGAR metabolic axis in the maintenance of Fanconi anemia hematopoietic stem cells,” Wei Du, MD, PhD, assistant professor in the School of Pharmacy at the West Virginia University Cancer Institute, and colleagues wrote in the study, published in Stem Cells.
Research conducted in animal models will lay the groundwork for a study in humans.
HemOnc Today spoke with Du about the research underway and the potential clinical implications of the findings.
Question: What prompted this research?
Answer: Fanconi anemia is a rare inherited disease characterized by bone marrow failure and high risk for neoplasia, including leukemia, from dysfunctional hematopoietic stem cells. Hematopoietic stem cell transplant is the only definite treatment for Fanconi anemia. However, for the margins it is very difficult to find a suitable donor, and the success rate is low even for those who receive a donor. Other ongoing research in Fanconi anemia is in gene therapy, because the gene related to this disease has been identified. It is known that gene-corrected cells grow better than Fanconi anemia-deficient cells. It was assumed that gene therapy would be beneficial for these patients, but the outcome was not promising —novel therapies appear to be needed earlier on. Our research focused on stem cell function in these patients, and we also sought to identify whether there is a metabolic change in Fanconi anemia.
Q: What did you find in animal models and how will this translate to humans?
A: Using knockout mouse models, we analyzed hematopoietic stem cells isolated from animals and found abnormal energy production pathways in mouse stem cells. We further analyzed the underlying mechanism and found overactivation of p53 and upregulation of its downstream factor in these stem cells. This plays a role in attenuating DNA damage resulting from Fanconi anemia mutation. However, it evokes a new problem for the stem cells and affects their function. In order to translate this data to humans, we think that balancing the skewed energy production in Fanconi anemia stem cells after gene correction would benefit the harvest of the gene-transferred cells and improve transplantation outcomes.
Q: Are there plans for a human trial?
A: It will be great to conduct a human clinical trial, but we would like to test this more in an animal model. We have isolated the defective stem cells from mice and can harvest the cells ex vivo after gene correction. Hopefully we can manipulate the energy production and infuse the cells back into the mice to see if this would improve the overall hematopoietic stem cell transplant.
Q: What do you hypothesize t hat you will find in a human trial ?
A: We know we have repeated this observation in mouse models. I would assume that this will be beneficial in humans, especially for gene therapy and transplantation. – by Jennifer Southall
Reference:
Xue Li, et al. Stem Cells. 2019;doi:10.1002/stem.3015.
For more information:
Wei Du, MD, PhD, can be reached at West Virginia University, P.O. Box 9530, BMRF Room 209, Morgantown, WV 26506; email: wei.du@hsc.wvu.edu.
Disclosure: Du reports no relevant financial disclosures.