To develop small molecules that correct metabolic dysfunction, specifically aberrant Fatty Acid Oxidation (FAO), which is a major pathophysiological feature of ALS.
Our drug discovery effort is nucleated around a new disease hypothesis for ALS – that when faced with a routine energy deficit, ALS-predisposed cells fail to respond correctly, and send themselves into a deadly spiral that is exacerbated by signals misconstrued as starvation, and which in turn lead to increased starvation. The correct response to an energy deficit (in neurons and in muscle cells) is to temporarily switch to burning Fatty Acids for energy, but to temper this process by initiating its shutdown almost as soon as it is activated. The incorrect response is to open the Fatty Acid import valve and forget to close it. We discovered that Stress Granules (SGs) are responsible for closing the Fatty Acid import valve, and as their function is disrupted in ALS, so is this critical metabolic response mechanism. This dysfunction can come about either because of a loss of function OR toxic gain of function of key SG and metabolic regulators, particularly TDP-43. By designing a metabolic “fingerprint” for ALS-related dysfunction, our therapeutic efforts can span the entire gain/loss of function spectrum of related mutations.
We investigated the metabolic response to fuel-deficit stress in ALS model cell lines and ALS patient-derived iPSCs differentiated to motor neurons.
Stress Granules associate with the mitochondrial porin, VDAC2, and regulate the gating of Fatty Acid import, the limiting factor for FAO. Stress Granule pathology and TDP-43 pathology disrupt the gating and induce constitutive FAO.