Application of a quantitative systems pharmacology (QSP) model to evaluate xCT inhibition as a target for central nervous system diseases.
Aims: Neuronal excitotoxicity, often mediated by glutamate, has been implicated as a factor in a number of central nervous system (CNS) diseases. In order to improve the understanding of the role of the cysteine-glutamate transporter (xCT) in excitotoxicity and CNS diseases and the potential utility of xCT inhibitors, Sanofi and Rosa collaborated in the development of a CNS PhysioPD™ Research Platform, a QSP model that supported hypothesis generation and testing. The objectives of the project were to evaluate the degree of xCT inhibition required to reduce CNS glutamate levels below neurotoxic levels and retain normal microglial phagocytic function, and to provide guidance on the CNS indications most likely to respond to this mechanism of action.
Methods: The ordinary differential equations based Platform represented 1./ cell dynamics of microglia activation, neuronal stress and death 2./ synthesis/expression and metabolism of mediators and surface markers 3./ xCT function (amino acid transport) and dysfunction processes associated with multiple sclerosis (MS) and Alzheimer's disease and 4./ GSH metabolism in healthy white and gray matter) 5./ effects of treatment by xCT inhibitors.
Results: The developed Virtual Patients represent an initial extrapolation step toward in vivo representation to gain initial insights on the chances of maintaining healthy microglial function and reducing neurotoxicity by altering glutamate and cystine concentrations via inhibition of the xCT antiporter. Results from simulated xCT inhibition in the Platform supported the prioritization of MS as the lead therapeutic indication. Additionally, simulation research and insights led to focused recommendations for in vitro experiments to resolve material uncertainties in the understanding of xCT function and xCT inhibition and to reduce risk in the development program.
Conclusion: The Platform is a useful illustration of the key role that QSP modeling can play in providing quantitative integration of internal and external knowledge, mechanistic insight and support decisions already in early stage drug discovery.