Validating novel, selective CaV2.3 inhibitors as oral, small molecule therapies for posttraumatic stress disorder

Post-traumatic stress disorder is a prevalent mental health condition with significant unmet medical need. Over 5% of trauma-exposed adults worldwide develop PTSD during their lifetimes, with those exposed to certain types of trauma such as combat and assault carrying a particularly high burden. The few approved drug treatments (e.g. paroxetine and sertraline) have limited efficacy and significant side effects. A recently published multi-ancestry meta-analysis of genetic data from >1 million individuals exposed to trauma reported significant risk of PTSD associated with the CACNA1E gene which encodes a voltage-gated calcium channel (CaV2.3) with high expression in brain areas (hippocampus, amygdala, anterior cingulate and prefrontal cortex) involved in memory, emotional regulation, and stress response. Genome-wide analyses of transcription indicated that the highest risk alleles are linked to significantly higher expression of CACNA1E, suggesting that inhibition of CaV2.3 function has potential therapeutic benefit. Lario Therapeutics has developed first-in-class, small molecule inhibitors of CaV2.3 which are potent, selective, and brain-penetrant. This collaborative proposal aims to validate CaV2.3 as a target for PTSD and to test potential CaV2.3-targeted therapeutics in mouse models of PTSD including stress-induced alterations in anxiety, fear conditioning and in paradigms showing learned flexibility of instinctual fear behaviours.