Project Details
Projekt
In vitro CHIP modelling for therapeutics discovery and mechanistic dissection (project A4)
Applicant
Professor Jaya Krishnan, Ph.D.
Subject Area
Cardiology, Angiology
Hematology, Oncology
Hematology, Oncology
Term
since 2023
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 515629962
Clonal hematopoiesis of indeterminate potential (CHIP) occurs due to acquisition of somatic mutations in hematopoietic cells in the absence of detectable hematologic malignancy, affecting approximately 10-40% of both men and women aged 65 years and above. The most frequently mutated clonal hematopoiesis (CH) genes code for the epigenetic modifiers Tet methylcytosine dioxygenase 2 (TET2) and DNA methyltransferase 3A (DNMT3A). Chronic heart failure patients with TET2 or DNMT3A mutations with a variant allele frequency (VAF) >= 2% show accelerated disease progression and mortality. CHIP is associated with increased all-cause mortality, predisposition to myocardial infarction, coronary heart disease and cardiovascular disease development. Studies in preclinical models indicate that TET2 and DNMT3A mutations in myeloid cells promote cardiac inflammation and dysfunction leading to heart failure and death. Given the lack of effective therapies for cardio-inflammatory CHIP and the significant unmet need, the key objective of this project proposal is to identify, mechanistically dissect and develop effective therapies for TET2 and DNMT3A CHIP for clinical translation. In previous work, synthetic lethality screening of EMA/FDA-approved compounds uncovered Lanatoside C as a potent negative modular TET2-deficient myeloid cell viability. To confirm these effects in patients, we aim to study the impact of Lanatoside C on TET2 and non-TET2 CHIP patient myeloid cells. Recapitulation of our previous findings in the patient setting will provide greater evidence and rationale for clinical translation. Further, we will test the efficacy of Lanatoside C at different doses in mouse models of mutant TET2 CHIP. These studies will reveal the physiologic impact of Lanatoside C on disease development and progression and will provide insight into optimal dose for translation. Finally, we aim to dissect signaling crosstalk underlying Lanatoside C action specifically in TET2-deficient cells. Given the high unmet need for DNMT3A CHIP therapies, we aim to similarly identify efficacious EMA/FDA-approved compounds specifically targeting DNMT3A mutant myeloid cell viability through synthetic lethality screening. We will first establish the mutant DNMT3A CHIP model through generation of DNMT3A loss-of-function siRNA and mutant CRIPSR/Cas lines in human myeloid cells. Upon model characterization and benchmarking to DNMT3A CHIP clinical data, we will initiate synthetic lethality screens against EMA/FDA-approved compounds. In doing so, we aim to uncover repositioning drug candidates for treatment of DNMT3A cardio-inflammatory CHIP. Taken together, the proposed project has the potential to uncover already approved drugs for treatment of cardio-inflammatory CHIP. This approach minimizes development timelines and costs in bringing the therapy to clinics and may serve to meet the global significant unmet need for cardio-inflammatory CHIP therapies.
DFG Programme
Research Units
