Validation of the spadin concept for the treatment of depression – VASPAC

Depression is a polygenic and highly complex psychiatric disorder that is currently a major burden on society. Depression is highly heterogeneous in presentation and frequently exhibits high comorbidity with other psychiatric and somatic deficits. Commonly used treatments, such as selective serotonin reuptake inhibitors (SSRIs), are not ideal since only a subset of patients achieve remission. In addition, the reason why some individuals responds to antidepressants (ADs) while others don't is unknown. Understanding the neurobiological basis of depression and improving the therapeutic strategies remains one of the foremost challenges for modern psychiatry. In 2006, Heurteaux's group demonstrated that TREK-1 channel is a new target against depression and its inhibitors as putative ADs. In 2010 Mazella's team in collaboration with Heurteaux's team has identified spadin as a specific blocker of TREK-1 with particular AD properties. The first aim of this ANR project is to definitively validate the concept of spadin, a natural peptide derived from the propeptide released by furin during the maturation of the sortilin receptor for the treatment of depression. The validation of spadin as potent AD of new generation will be developed from the use of specific models of depression (chronic mild stress, administration of chronic glucocorticoids, early-life blockade of the 5-HT Transporter, non-helpless (NH/Rouen) and helpless (H/Rouen) mice). The existence of TREK-1/Sortilin/ Spadin complex has been recently discovered. It is the reason why the second aim of this program is to better understand the regulation of this biological system which can regulate important physiological functions such as regulation of mood and glucose homeostasis by using three mutant mouse lines (KCNK2-/- , Sort1-/- and KCNK2-/-/Sort1-/- mice).
The third objective of the ANR project aims at validating in humans the spadin, sortilin and TREK-1 channel as biomarkers for depression. As new neuroscience discoveries increased our poor knowledge of the neurobiology of mood disorders and their treatment, biomarkers have come to seem possible and even inevitable. But despite all the enthusiasm, we have yet to see specific biomarkers used in clinic. The single biggest hurdle is that many of the recent discoveries have been established in animal models, and translating them to humans has been very difficult. This ANR project has the ambition to characterize in humans the peripheral blood transcriptional signature with a focus on SORT1 and KCNK2 genes and to develop the seric dosage of spadin in comparison to 2 other proteins BDNF and CRP, widely recognized as reflecting the pathogenesis of MDD. Because, so far, no serum/plasma marker used to potentially diagnose MDD is specific to the disease and because spadin is an endogenous and natural peptide it could be revealed itself, in human subjects, as an endogenous AD marker. These approaches may help to discriminate major depression patients from control individuals but more importantly responders from non-responders to antidepressant therapy.
This proposal will address these three main issues by using a combination of behavioral, electrophysiological, biochemical and genetical approaches on adequate transgenic mouse models and the aperture on clinic with the exploration of depressive patients and the search of biomarkers of depression. As an ultimate goal, it is expected that this project will allow in the future the development of exploratory clinical trials with the use of spadin, as both a potent endogenous peptidic AD drug with an improved efficacy devoid of side effects, as well as a biological marker for depression diagnosis. Therefore, this program aims to open a new field in the therapeutic treatment of depressive disorders.