Grant: Proof of Principle Program - Phase I

Major depressive disorder (MDD) causes significant morbidity and mortality, and has profoundly disabling effects on functioning. In the developed world, MDD causes the most years of life lost to disability of any disease. With current treatment, only 1/3 of patients achieve full remission of their symptoms after a single trial of antidepressant medications. Even with multiple antidepressant trials, 10-15% of patients continue to experience depressive symptoms and there are few alternatives available for these patients. New and better antidepressant treatments are clearly needed. Over the last 10 years, my lab has focused on identifying specific pathways underlying pathological conditions. We have found that the coupling between two proteins in brain called dopamine D1 receptors (D1R) and D2 receptors (D2R) are abnormally enhanced in patients suffering from MDD. We therefore developed a short protein peptide that can block the D1R-D2R coupling. We have found that administration of this peptide into the brain of rat models of depression exerts antidepressant effects (Pei et al., 2010 Nature Medicine, Appendix 1). With further work, we believe that this peptide may represent a breakthrough in the treatment of MDD, with enhanced efficacy and fewer side-effects than existing antidepressants. In the current application, we propose to work with Impel NeuroPharma to administer this peptide to the nasal cavity in order to enable direct distribution to the brain. Intranasal administration is a non-invasive and clinically viable method for delivering effective concentrations of the peptide to the brain. We will investigate the safety, dosage and efficacy of our intranasally administered peptide. This approach will represent a secure developmental pipeline to commercialize our peptide therapeutics as rapidly as possible within the pharmaceutical sector, given the high degree of novelty and innovation in our initial discovery.