Individualizing cardiovascular therapies and the role of single cell proteomics

Underlying precision medicine is the concept that an individual’s Omic (proteomic) signature will provide a physician with clinically actionable diagnosis and subsequently, a mechanistic therapeutic route. However, our newest data indicates that drugs may not equally alter the proteome across all single cells within the target organ. This raises the possibility cell’s proteome dictates drug responsive and thus, drug effectiveness would be dictated by number of cells in the “correct responsive” proteomic state. To address this we have moved to single cell proteomic analysis using iPSC-cardiomyocyte culture that we have been utilizing for drug screening. First, we established a workflow to analyze single cell proteomes of human iPSC at various times during differentiation into cardiomyocytes. We established the maturity of the ISPC-derived cardiomyocytes based on comparison to single cells isolated from adult human hearts. Second, we treated the “mature” ISPC-derived cardiomyocytes with various drugs, including a novel drug that activates Parkin which in animals protect the heart from injury. We have also established the proteomic profile of single cell drug-responsiveness. Next, we are attempting to shift the baseline proteome of non-responsive cells into a responsive state to promote a broader drug effectiveness. To promote this we have been adapting our scalable high-through methods for mechanistic drug screening on IPSC-derived cardiac cells across many individuals to determine the genetic effects on drug-responsive single cell heterogeneity. In conclusion, our single cell data highlights the need to understand the single cell heterogeneity with respect to drug responsiveness must be addressed as part of identifying treatable clinical routes for a particular person.