Single Cell Foundation Model enabled drug discovery for clonal hematopoiesis

Project Summary
Aging is associated with increased mortality and the prevalence of diseases such as
cancer, cardiovascular, neurological, and respiratory diseases. One fundamental
mechanism of aging is acquiring DNA mutations, which can lead to clonal hematopoiesis
of indeterminate potential (CHIP), frequently driven by mutations in in DNMT3A, TET2, and
ASXL 1. We seek to identify and re purpose existing medications or investigational
therapeutics to decrease or eliminate the CHIP clone as a way to address multiple agingrelated
diseases. We will leverage single cell machine learning foundation models, human
genetics, and electronic health records (EHR). We propose a two-phase approach: In the
UG3 phase, we will utilize single cell foundation models to perform virtual screens as well
as genetic and EHR data to identify existing medications to reverse CHIP pathology. In the
UH3 phase, we will experimentally validate drug candidates in in vitro and in vivo CHIP
models. Successful execution of this work will rapidly translate findings into the clinic by
repurposing FDA-approved medications to mitigate CHIP and its related aging diseases.

Grant Number: 1UG3AG097155-01
NIH Institute/Center: NIH
Principal Investigator: Alexander Bick