Neuronal Population Models Reveal Specific Linear Conductance Controllers Sufficient to Rescue Preclinical Disease Phenotypes

Abstract

Objective: During the preclinical phase of drug development, potential drug candidates are often screened for their ability to alleviate certain in vitro electrophysiological features among neurons. This ability is assessed by measuring treatment outcomes using the population mean, both across different cells and different animals. The go/no-go decision for progressing a drug to a clinical trial is then based on ‘average effects’, yet these measures may not be sufficient to mitigate clinical end point risk. Population-based modeling is widely used to represent the intrinsic variability of electrophysiological features among healthy, disease and drug treated neuronal phenotypes. We pursued a method for optimizing therapeutic target design by identifying a single coherent set of ion channel targets for recovery of the healthy (Wild type) cellular phenotype simultaneously across multiple measures. Specifically, we aimed to determine the set of target modulations that best recover a heterogeneous Huntington’s disease (HD) population of model neurons into a multivariate region of phenotypic measurements corresponding to the healthy excitability profile of a heterogenous Wild type (WT) population of model neurons. Methods: Our approach combines mechanistic simulations with populations modeling of striatal neurons using evolutionary algorithms for population optimization to design ‘virtual drugs’. We introduce efficacy metrics to score population of model outcomes and use these to rank our virtual candidates. Results: We found that virtual drugs identified using heuristic approaches performed better than single target modulators and those derived from standard classification methods. We compare a real drug to the virtual candidates and demonstrate a novel in silico triaging method.