The Way Forward for Mechanism-Based Therapeutics in Genetically Defined Neurodevelopmental Disorders

Abstract

Rare genetically defined neurodevelopmental disorders with increased risk of autism have recently become an entry point for autism-related drug discovery. Through exploration of downstream effects of the pathological mutations, specific mechanistic pathways have been identified as dysregulated. The identification of shared mechanisms across forms of autism opens the door for the development of novel "mechanism-based therapeutics." However, confidence in the therapeutic mechanism does not diminish the need for well-designed clinical trials.

Figure 1:

MRI based biomarker of ASD diagnosis in children with TSC. Representative illustrations of the projections of the corpus callosum in a child with TSC and ASD (A. TSC ASD+), only TSC (B. TSC ASD-) and a typically developing child (C. Control) demonstrating a sparsity of connections in children with TSC and ASD relative to the other groups. Treatment with everolimus increases fractional anisotropy, a marker of white matter connectivity, in patients with TSC(D). Figure 1, panels a, b, c are adapted with permission from Peters, J. M. et al. Loss of white matter microstructural integrity is associated with adverse neurological outcome in tuberous sclerosis complex. Acad Radiol 19, 17–25, doi:10.1016/j.acra.2011.08.016 (2012). Figure 1, panel d is adapted with permission from Tillema, J. M., Leach, J. L., Krueger, D. A. & Franz, D. N. Everolimus alters white matter diffusion in tuberous sclerosis complex. Neurology 78, 526–531, doi:10.1212/WNL.0b013e318247ca8d (2012).