Medication of a new concept on depression – MEDINCOD

The aim of the project is the development of a new treatment for depression. Depression is a disease particularly frequent which can reach to 20% of the population in the industrial countries. The numerous origins of this pathology involving multiple genes as well as environmental and developmental components lead to a disorder which remains difficult to counteract. Several therapies for depression have been developped, they target monoamine neurotransmitters since deficiencies in 5-hydroxytryptamine (5-HT, serotonin) or in adrenaline in the brain are postulated to be responsible for the appearance of the illness. Therefore, most treatments are selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine, paroxetine or sertraline, and serotonin-noradrenaline reuptake inhibitors (SNRIs) such as duloxetine and venlaxine. Tricyclic antidepressants (ADs) such as imipramine and amitriptyline are also widely used. However, these treatments are not only associated with numerous undesired effects such as weight gain, nausea, and anhedonia, but they are also globally inefficient for more than one third of patients. The resulting consequence of all these problems is the frequent arrest or misadministration of the treatment by the patients themself. Therefore, the necessity to find and to develop a new concept to treat depression appears crucial.
The present project could lead to the effective use of a new type of AD embedded in a new concept to deliver the active molecule for a chronic treatment. Recently, from a work realized in collaboration between our group and the group of Catherine Heurteaux, we characterized the ability of the peptide spadin released from the maturation of the neurotensin receptor-3 (also called sortilin) to block the activity of the potassium channel TREK-1, an identified target in depression. The AD activity of this peptide, named spadin, has been demonstrated using several different behavioral tests in mice.
The first objective of the project is to validate a method to deliver the peptide for a several weeks treatment using a Medingel biopolymer formulation. This approach, consisting to embed the peptide in a formulation injectable subcutaneously, should allow to avoid problems raised by classical treatments which are constraining by repeated absorption of the medication. The validation will consist to measure the efficiency of injected formulation to trigger AD effect in specific mouse model of depression, and to verify the absence of side effects following this treatment.
The second goal of the project will be the research of adverse effects, mutagenicity and toxicity of the spadin formulation which could be proposed in a future clinical phase 1 trial. This will be done by the CERB company by measuring the most frequent adverse effects as early as possible in rats and guinea pigs. On the other hand, we will verify the effects of the spadin or analogues formulations on the peripheral tissues expressing the targets of the peptide (ie: liver, skeletic muscle, pancreas).