Modeling Clonal Hematopoiesis and Genetic Correction in RUNX1-FPD Using Human iPSC-derived HSCs
Patients with RUNX1-FPD often acquire secondary mutations that increase the risk of disease progression. It is likely that some of these secondary mutations confer more of a risk than others. This risk may also be modified by other factors, such as infections, medications and lifestyle. Currently, we do not understand well the risk associated with each type of mutation and how to modify it. We do not have ways to interfere early in order to prevent or slow progression of the disease to premalignant or malignant stages.
In addition, RUNX1-FPD, as a genetic disease caused by a defined mutation in a single gene, is in principle amenable to genetic correction. Such an intervention, if feasible, could provide a definitive and permanent cure with a “one-and-done” treatment. However, currently, many questions remain that render the feasibility of such an approach very uncertain. While several technological breakthroughs have created technologies that can support such an effective and safe therapy, a major unknown is whether gene-corrected hematopoietic stem cells would be outcompeted by mutant cells, effectively precluding a successful therapeutic outcome. In contrast, if corrected cells have an advantage over the mutant cells, they would expand and gradually take over the bone marrow, eliminating the mutant cells and restoring normal hematopoiesis.
Project Goals
This project was two main goals.
First, we will generate novel models of secondary mutations in RUNX1-FPD and co-transplant them together with RUNX1-FPD hematopoietic cells into mice. These models will allow us to study for the first time with human cells the factors that promote the growth of mutant cells and test interventions, including existing FDA-approved drugs, for their ability to slow or prevent their growth. Such drugs would be predicted to be beneficial in preventing disease progression in RUNX1-FPD patients and, therefore, these results can directly lead to clinical trials to test them.
Second, we will generate novel models of genetic correction of RUNX1-FPD and, again, test for the first time with human cells, whether corrected cells can outcompete the mutant cells, or, alternatively, are outgrown by them. These results will inform future approaches towards the development of permanent gene correction therapies for RUNX1-FPD.
