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CHOP Physician-Scientist in Search of Cure for Fanconi Anemia

Published on October 15, 2020 in Cornerstone Blog · Last Updated 3 years 1 month ago


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Fanconi anemia, a rare genetic disease, presents with low blood counts due to rapidly declining blood producing stem cells in the bone marrow.

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Loss of blood cell production is part of the daunting diagnosis of Fanconi anemia (FA), a rare, inherited DNA repair disorder with prominent hematologic complications. Caused by a mutation in FA genes, the condition presents with low blood counts on the basis of rapidly declining blood producing stem cells in the bone marrow.

Young children with FA experience bruising, nose and gum bleeds, infections, and unexplained fatigue. FA shows up first in the blood and bone marrow, but it’s a chronic disease that can affect many of the body’s organ systems (such as heart, skin, gastrointestinal), and is associated with a heightened risk of cancer as patients enter their 20s and 30s. Regular, lifelong monitoring is necessary.

FA’s early manifestation and chronicity led physician-scientist Peter Kurre, MD, director of the Comprehensive Bone Marrow Failure Clinic at CHOP, to search for the cause and cure for this disorder. His multidisciplinary team combines clinical care and basic research to understand the causes of bone marrow failure syndromes, of which FA is one, and to develop new therapies.

Dr. Kurre received a grant from the National Heart, Lung, and Blood Institute to work with murine models to determine the size of the stem cell pool at different stages of development and after birth to identify how large the stem cell deficits are with which FA patients start. They also aim to describe the detailed mechanism by which these stem cells fail, and to begin to think about some potential options for how to address the deficits that they find to help exploit the mechanism into working properly.

“We’re all endowed with a limited number of stem cells, essentially fixed at birth or soon thereafter,” said Dr. Kurre who is also on faculty at the Perelman School of Medicine at the University of Pennsylvania. “So if during fetal life, you don’t make enough, that’s a big problem. It’s clear to us now that when kids first come to see us in clinic, usually around age 8, they have already lost a majority of their blood forming stem cells. The horse is out of the barn at that point, the process starts much earlier — in utero.”

Addressing the Deficits

The new grant builds on previously published research of the Kurre Lab. By studying development in mouse models that represent FA, the team determined that significant abnormalities were already present in fetal hematopoietic stem cells (HSC). These were novel findings because, until that point, researchers did not know where the process of failure started. In this project, they hope to determine to what extent the defects in fetal blood forming cells accelerate the loss of bone marrow function in young patients.

“The deficits that we’ve already measured in published data are pervasive,” Dr. Kurre said, “so I expect there to be a significant defect. But, the tools we’ve used so far weren’t sufficient to comment on the size and remaining ability of the stem cell pool to maintain safe blood counts.”

By collaborating with the Center for Single Cell Biology, and senior bioinformatics co-investigator, Zhe Zhang, PhD, MSF, they will be rolling out genetic tools working with mouse models that will allow the researchers to come up with a definitive answer to the question that’s been nagging the scientific field: How large are the actual HSC deficits in FA?

Damaged: Do Not Repair

They plan to dig deeper into their findings that describe the underlying mechanism, which is causing the stem cell deficit. Healthy people’s cells typically repair any DNA damage, but in people with FA’s cells, some of those repair programs don’t exist. Instead, in FA, the fetal stem cell generates signals from the accruing damage. These signals tell the cell not to make more and stop expanding the stem cells. Not making any more damaged cells is the intended outcome, but the net effect is that not enough are made to last a lifetime.

“The signal is basically saying, ‘The risk for more mutations is too high. We need to stop cycling and wait for good quality control to kick in,’ which in FA, it never does,” Dr. Kurre explained. “This, in a nutshell, is the problem.”

Dr. Kurre and his team are looking for therapies that will allow the stem cells to continue to cycle, build a better stem cell pool without collecting mutations, and eventually lead to the delay or rescue of hematopoietic failure in FA patients.

“We’ve been looking at cures that go beyond transfusing blood cells and that are not as potentially fraught with complications as a bone marrow stem cell transplantation,” Dr. Kurre said. “Having found this mechanism, we’re trying to understand if there is a way to bypass this bottleneck and get the cell to make additional stem cells to increase the pool size in a way that is safe.”

To learn more about next steps visit the Fanconi Anemia Research Fund.