Micro RNAs to Treat Depression

The DemiRNApy project “Depression: the role and modulation of miRNAs in the anterior cingulate cortex as peripheral biomarkers and targets for promising nanotherapies” is one of the research projects that has received funding from the Fundació Marató TV3 charitable fundraising drive in its 2021 edition dedicated to mental health. Out of a total of 150 submitted projects, the Agency for Health Quality and Evaluation with the Government of Catalonia’s Department of Health chose 36 to receive funding for three years.

DemiRNApy is being coordinated by Dr Analía Bortolozzi, a researcher with the Institute of Biomedical Research of Barcelona – CSIC and a specialist in the study of miRNAs (micro RNAs) in severe neuro-psychiatric disorders such as depression. Dr Cristina Fornaguera, with the Materials Engineering Group (GEMAT) at IQS, and Dr Francisco Javier de Diego, a psychiatrist at the Hospital de la Santa Creu i Sant Pau Research Institute Foundation, are also participating in the project.

Major depressive disorder

Major Depressive Disorder (MDD) is a complex disorder of brain networks that leads to abnormal information processing in the circuits that regulate mood, emotion, and cognition, with the underlying molecular and cellular mechanisms hardly understood.

The DemiRNApy project stems from previous research which has found that the altered expression of miRNAs – small noncoding RNAs that are regulators of synaptic and neuroplasticity functions – in the anterior cingulate cortex (ACC) plays a critical role in the development of major depressive disorder. Recently, altered levels of some of these miRNAs have been reported to affect the expression of crucial target mRNAs involved in affective, or mood, disorders.

miRNAs as the future of MDD treatments

MiRNAs appear to hold great promise as biomarkers of disease and response to treatment, as well as molecular targets for the development of new therapeutic strategies. In view of the deregulation of miRNAs observed in patients with MDD, the goal of DemiRNApy is to aim to modulate them to try to establish a therapy that can return them to the levels of healthy people, thus preventing the risk of suicidal behaviours, one of the worst consequences associated with depressive disorder.

First, the teams at the IibB  and the Hospital de la Santa Creu i Sant Pau will identify and define in a clinical and preclinical phase the miRNAs involved in depressive disorder both in human patients – in order to treat them later – and in mice with an alteration in the cingulate cortex – to produce preclinical models with which new therapies can be tested. Once the deregulated miRNAs have been defined, it will be possible to move on to the therapy phase.

However, this genetic material cannot be administered on its own since it degrades. In this case, it is also necessary for it to act in the central nervous system in the anterior cingulate cortex, the area of the brain that has the most relevant role in depression and the risk of suicide. Thus, once the miRNAs that will be used are known, the IQS team will contribute its experience in the encapsulation of genetic material in nanoparticles (NPs) that will be designed for this purpose to be able to reach the anterior cingulate cortex and the miRNAs to access the cells in which they must act. The GEMAT team at IQS, composed of Dr Cristina Fornaguera, Dr Salvador Borrós, Dr Marta Guerra, and Dr Rodrigo Maraña, has extensive prior experience in the development of NPs that are capable of crossing the blood-brain barrier.

In this way, once the cocktail of necessary miRNAs is defined, they will be encapsulated in the NPs designed by the GEMAT group at IQS and studied in animal models if they indeed reach the brain, to confirm preliminary studies, and once they arrive if they can reverse the depression phenotype.

This project has many advantages as the therapies currently used are highly invasive and directly administrated to the brain. DemiRNApy therefore provides another approach that will enable a turning point for MDD patients from diagnosis to therapy.