RNA therapeutics for mood disorders: current evidence toward clinical trials

ABSTRACT

Introduction

Mood disorders are severe yet frequent psychiatric disorders worldwide, comprising major depressive disorder (MDD) and bipolar disorders (BD). Their treatment remains poorly effective. Recently, growing evidence for epigenetic mechanisms has emerged. Consequently, a great interest in a novel pharmacological class arose: RNA therapeutics.

Areas covered

We conducted a systematic review of RNA therapeutics -antisense oligonucleotides (ASOs), small interfering RNAs (siRNAs), short hairpin RNAs (shRNAs), and micro-RNA (miRNA) therapeutics- for the treatment of mood disorders studied in pre-clinical animal models listed in PubMed, in clinical trials registered in ClinicalTrials.gov and available on the market by combining literature search and Food and Drug Administration and European Medicine Agency online databases. Eighteen pre-clinical studies investigated the antidepressant effects of RNA therapeutics. However, even though there is an increasing number of marketing authorizations and clinical trials for the past twenty years, no RNA therapeutic has reached the clinical development pipeline for the treatment of psychiatric disorders yet.

Expert opinion

Several promising RNA therapeutics have been tested in pre-clinical studies for MDD, whereas no molecule has been developed for BD. There are several issues to address before reaching clinical development and new challenges include stratifying patient population and predicting therapeutic response.

KEYWORDS:

• Depression
• antisense oligonucleotide
• small interfering rna
• animal model
• epigenetic

Article highlights

• Up to 30% of patients suffering from mood disorders are resistant to conventional treatments

• RNA-based drugs acting on epigenetic events, called RNA therapeutics, are on the rise

• A systematic review of preclinical studies assessing RNA therapeutics on depression-like behaviour of animal models revealed several promising molecules: five ASOs, six shRNAs, eight siRNAs, one miRNA mimic and one anti-miRNA

• One promising delivery strategy using small molecules binding to specific neurotransmitter transporters and conjugated to RNA therapeutics ensures selective delivery to the targeted neurons after intranasal administration

• While phase I, II and III studies evaluate several RNA therapeutics for the treatment of various neurological disorders, no clinical trial tested RNA therapeutics for the treatment of mood disorder

• Several issues regarding efficacy, toxicity, safety and economic matters must be addressed before RNA therapeutics can reach clinical development for the treatment of mood disorders

Disclosure statement

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.