Seminar invitation: Simulation-based identification of optimal molecular targets for Spinal Muscular AtrophyAbstract

Spinal Muscular Atrophy (SMA) is the second leading genetic cause of infant mortality. Homozygous absence of the Survival Motor Neuron 1 (SMN1) gene is the cause of SMA, while SMA severity is mainly determined by the number of SMN2 copies. It was reported that the severity of SMA can be essentially alleviated by an increase of SMN2 mRNA and SMN protein concentrations through inhibiting HDAC – the major molecular regulator of SMN production pathway. SAHA, VPA, TSA and resveratrol are potential drugs that increase SMN2 mRNA and SMN protein concentrations by inhibiting HDAC. Wet lab experiments show that use of these chemicals in SMA patients lead to 1.3- to 2.7-fold increase of SMN protein. In the present research, we create deterministic model of SMN production pathway, perform computational validation of underlying pathway by known wet lab observations, and use model checking technique to determine an optimal combination of these potential drugs that leads to the maximum induction of SMN protein. The simulation results show that SMN concentration can be increased up to 3.84-fold over the control. The current work is conducted in terms of hybrid Petri nets on Snoopy platform. Proposed technique can be easily adapted to other disorders as well.