A Systems Biology Approach to Enable Safe Administration of Mefloquine

Mefloquine is known to cause adverse neurological effects, possibly attributable to single nucleotide polymorphisms (SNPs). Our objective is to develop a genetic screen capable of determining the susceptibility of an individual to Mefloquine neurotoxicity. In Phase I, transcriptional profiling of primary neurons exposed to Mefloquine was used to construct an intracellular pathway model to explain the observed neurotoxicity. Analytical tools were then used to identify potential SNP target candidates, followed by RNAi methods to validate the potential SNP targets. The Phase II effort will begin with an expansion of the pathway scope, including all known information. Analysis tools will be enhanced with new capabilities for capturing regulation and feedback effects, and additional SNP targets will be identified. Experimental validation will be performed by verifying functionality using a battery of measurements of cellular function (oxidative stress, apoptosis among others). Simultaneously, a prospective pilot clinical study will be performed to specifically examine linkages between reported MFQ adverse side effects and identified SNPs. The Phase II project will establish the groundwork for a Phase III effort, including a prospective, double blind, placebo controlled trial followed by development and commercialization of a genetic screen.