Significant potential for microRNA blood tests for psychiatric disorders

Their therapeutic potential is still be limited, but the overlap between these small non-coding RNA sequences in blood and brain may mean significant potential for biomarkers and diagnostics, says our expert.

Depression and anxiety are just two examples of psychiatric disorders where microRNAs have pathological roles. Anand Gururajan (@anandgururajan), behavioural pharmacologist at University College Cork looks at their potential as biomarkers for the diagnosis and their utility as therapeutic targets. We spoke with him about progress in the field.

ResearchGate: What do we know of microRNA’s role in psychiatric disorders so far?

Anand Gururajan: Recent advances in genomic technologies have significantly improved our ability to investigate the molecular neuropathology of various psychiatric disorders. This includes the identification of microRNAs which are small non-coding RNA sequences that negatively regulate gene expression, although there is evidence to suggest that some enhance gene expression.

Several clinical investigations have shown that microRNA expression is dysregulated in patients with psychiatric disorders such as depression, schizophrenia and PTSD. This dysregulation has been shown to correlate with the expression of previously known downstream mediators of disease pathology, and symptomatology. Importantly, some studies have also reported normalisation of expression following treatment.

But what is perhaps most exciting and relevant in the context of biomarkers is that there is a high degree of overlap between microRNAs expressed in both the blood and the brain. As such, there is significant potential for the use of blood-tests to analyse microRNA levels in conjunction with existing metrics to more objectively diagnose psychiatric disorders and personalise treatment strategies.

RG: What role do you think will microRNA play in the treatment of psychiatric disorders in the future?

Gururajan: As it stands, the therapeutic potential of microRNAs in psychiatry is limited for two main reasons. Firstly, microRNAs are promiscuous in their activity; each microRNA can target several different messenger RNA (mRNA) sequences and each mRNA is the target of several microRNAs. So there is a need to take into account off-target effects of artificially up- or down-regulating microRNA expression on neuronal gene networks unrelated to the disease. Related to this issue, microRNAs have relatively subtle effects on their downstream targets, but these effects may be significant and even detrimental if their expression exceeds specific tolerances. Secondly, delivery of microRNA-based therapeutics directly into the brain in a cell- or region-specific manner is a significant challenge, but which could potentially be overcome by the use of formulation strategies including nanoparticles.

RG: What can you tell us about therapies in development?

Gururajan: There is an active drug discovery pipeline for microRNA-based therapies in other medical specialities such as cardiology, oncology and infectious diseases. Psychiatry lags behind but the rapid pace of research in this field is likely to challenge the status quo in the near future.

RG: What will it take to make the next steps?

Gururajan: I'd like to think that we are in epoch that is marked by the renaissance of RNA biology.  In particular, the wide-ranging and influential role of non-coding RNA species has cast new light on the regulatory mechanisms of gene expression in the human body in healthy and disease states. These include microRNAs as well as long non-coding RNAs which can act to either suppress or enhance gene expression. The emerging field of epitranscriptomics, the over-arching term used to describe the biochemical modifications, editing and changes to structure and localisation of RNA sequences, influencing their function, adds another layer of complexity to the RNA landscape.

Over the coming years, the development of high-resolution transcriptomic technologies such as single-cell RNA-seq will reveal new and novel insights into the pathology of psychiatric disorders.  Concomitantly, advances in drug delivery technologies will allow for their translation into clinical RNA-based therapeutic strategies which hopefully improve quality of life for sufferers world-wide.