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  1. Advancing Regulatory Science

Identify Genotype-Phenotype and Pharmacogenetic Association Using a Population-scale Cellular Platform

CERSI Collaborators: Stanford University: Joseph C. Wu, MD, PhD

FDA Collaborators: Center for Drug Evaluation and Research: Rodney Rouse, DVM, MBA, PhD; David Strauss, MD, PhD; Kevin Ford, PhD

Project Start Date: August 25, 2022

Regulatory Science Challenge

A significant number of common and unusual alleles, or alternative forms or versions of genes, found in human populations impact the regulation and expression of human genes. The genetic diversity across individuals frequently results in a failure to find a treatment effect of an investigational drug in later stages of a clinical trial. As a result, genetic diversity should be considered not only during the early phases of drug discovery, but also throughout the drug development process. However, little is understood about how genetic differences impact human disease phenotypes, and much less about how combinations of these variations affect disease development and drug responses in patients. Understanding genetic variability across patients and how it impacts their reactions to drugswas previously thought to be too difficult due to expensive scale-up costs and a lack of rigor in clinical trials due to noise.

Project Description and Goals

The goal of this project is to perform applied research on lamin A/C (LMNA)-related dilated cardiomyopathy (DCM) in order to create a broadly applicable cellular platform for assessing the genetic variability of hereditary disease and drug responses. This platform will be based on a patient-specific cell model, multiplex single-cell RNA sequencing (scRNA-seq), and computational algorithms based on natural genetic variation across patients. This platform will be used to identify the clinical features associated with different LMNA gene mutations, as well as the differences in drug responses associated with different LMNA mutations. This project's long-term goal is to develop a population-scale cellular platform that can be standardized, shared, and widely used in drug development communities for various genetic conditions, including but not limited to LMNA-related DCM.

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