How RNA therapeutics are shaping the future of mental health treatment

This Mental Health Awareness Week, we wanted to highlight how the fast-moving field of RNA therapeutics is being leveraged to treat mental health disorders such as anxiety and depression. We will cover some of the RNA technologies being investigated for such indications, the current limitations of using RNA to treat mental health diseases, and how the crossover of RNA therapeutics into the mental health sector is reflected in the patent landscape.
 
RNA therapeutics have many benefits. As discussed in our previous articles (which you can read here and here), one of these is the ability to design them to specifically target many different ligands, including those which were previously considered “undruggable”. As a result, RNA can be used to treat many different diseases, including rare genetic diseases and numerous types of cancer. However, until recently, this technology has not been used for the treatment of any mental health disorders.
 
There are a few reasons why this might be. Firstly, delivery is a major obstacle for all RNA therapeutics and a large focus for research. Delivery of RNA therapeutics to treat mental health disorders is even more difficult because they may need to cross the blood-brain barrier to reach their target. Secondly, many mental health disorders are multifactorial and may be caused by both genetic and environmental factors. Mental health disorders which have genetic causes are likely to be linked to many genes. Therefore there may not be a unique gene for the RNA therapy to target. The risk of off-target effects may be increased if the correct target gene is not selected.
 

RNA therapeutics show promise for treating anxiety and mild cognitive impairment

In a recent study¹, scientists at Cognigenics demonstrated that RNA-based therapy can reduce anxiety and enhance memory in rodent models. The treatment used a short-hairpin RNA (shRNA), COG-201, to reduce expression of the serotonin 5HT-2A receptor in the brain. This receptor is expressed widely throughout the central nervous system and plays a role in memory, learning, and behaviour. As 5-HT2A receptor activity is associated with both anxiety and memory, researchers are hopeful this could be a more comprehensive treatment for both anxiety and mild cognitive impairment (which is defined as an intermediate state between normal memory loss due to aging to dementia).
 
In this study, a DNA plasmid comprising the shRNA sequence was designed to target the human or mouse HTR2A RNA transcript, which encodes the 5HT-2A receptor. The shRNA sequence contains a targeting sequence, a stem-loop sequence and a passenger strand. The sequence was delivered to rodents intranasally, using a single adeno-associated vector (AAV), chosen for its ability to cross the blood-brain barrier and drive shRNA expression in the CNS. The DNA plasmid containing the shRNA sequence was delivered to cells by the AAV, then expressed in the nucleus before entering the cell’s endogenous processing pathway. This resulted in target mRNA cleavage and target gene silencing using the RISC complex. A benefit of using shRNA compared to other RNA therapeutics is its high transfection efficiency and resulting efficacy, due to its use of the cell’s endogenous RNA interference pathway.
 
The results of the Cognigenics study demonstrated that the use of AAVs containing shRNA lead to decreased expression of the 5-HT2A mRNA and 5HT-2A receptor protein, as well as a reduction of spontaneous electrical activity in neurons in vitro. COG-201 treatment was also shown to be effective in vivo. Mice treated with COG-201 showed a decrease in anxiety-like behaviour following 5 weeks of treatment, and both aged and young rats demonstrated an improvement in memory.
 
Although this study is limited to rodent models, the results demonstrate that shRNAs delivered using AAVs are a promising candidate for the treatment of anxiety and mild cognitive impairment in humans. Cognigenics is also investigating the use of CRISPR-based technologies to target the same 5-HT2A receptor for treatment of anxiety/mild cognitive impairment.
 

RNA therapeutics may also be used to treat other mental health disorders

Due to the adaptability of RNA, it stands to reason that similar approaches to those taken by Cognigenics could be used to target other proteins known to be involved in mental health disorders.
 
RNA therapeutics have shown promise for treating depression. Lou et al² showed that reduced expression of the microRNA miR-124 is associated with depressive-like behaviours in mice with chronic unpredictable mild stress (CUMS). Microinjection of a lentivirus comprising the miR-124 sequence led to upregulation of miR-124 in the hippocampus and attenuation of the depressive behaviours. Furthermore, Choi et al³ also demonstrated that chronic stress leads to depressive-like behaviours in mice. This study used siRNA to suppress TRH (thyrotropin-releasing hormone) in the basolateral amygdalar complex of mouse brains. Downregulation of TRH led to a block of stress-induced depressive symptoms.
 
As well as using RNA to directly treat the mental health disorders, RNA can be a great tool to improve the efficacy of existing treatments. For example, Fullana et al⁴. showed the use of small interfering RNA, conjugated to sertraline or reboxetine, induced a robust anti-depressant-like response in mice. The siRNA reduced the mRNA and protein levels of the TASK3 potassium channel, leading to due to the increase in sertraline or reboxetine accumulation in neurons. Last year, Circular Genomics received $8.3 Million in Series A investment to launch a test which detects circular RNA biomarkers, to identify the likelihood of a person living with depression to respond to SSRI treatment⁵.
 

How this research is reflected in the patent landscape

Due to the very recent development of RNA therapeutics in mental health treatment, there do not appear to be many published patent filings in this area. Those applications that we have identified are often in the very early stages. So, it is perhaps too early to tell what the filing trends are in this new and niche area of therapy. However, given the prevalence of mental health disorders and often limited treatment options, we expect to see more and more applications in this area.
 
The EPO’s usual rules for claiming a medical use will apply to patent applications directed to treating mental health disorders using RNA technologies. Possible claims may include product claims to a nucleic acid comprising the therapeutic RNA sequence, and a pharmaceutical composition comprising the same, as well as medical use claims directed to the nucleic acids and compositions for use in treating the mental health disorder in question. Our recent webinar “RNA technologies: pitfalls and patent drafting tips in Europe” provided excellent tips to use when drafting patent applications directed to RNA therapeutics to avoid common pitfalls. Please reach out to your usual Kilburn and Strode advisor if you would like a recording of this webinar, or to discuss the best strategies for drafting patent applications this area.
 
Although the use of RNA for treating mental health disorders is in the early stages, RNA technologies for the diagnosis of mental health disorders through the recognition of biomarkers is much more established. This is also reflected in the much greater number of patent applications directed to RNA for diagnosis. For example, there are applications for methods of screening for miRNAs as biomarkers for anxiety and depression. Further patent applications are directed to the determination of levels of fibroblast growth receptor 3 mRNA for the diagnosis, or evaluation of risk of schizophrenia.
 
The promising results demonstrated in the studies discussed in this article offer hope to those living with mental health disorders, who may have been faced with limited or ineffective treatment options. Although the development of RNA therapeutics for treating mental health disorders may still be in the early stages, perhaps the early investment and research in this area signals a future where mental health treatment options are more precise and personalised, and we hope more effective for those in need.

If you have any questions relating to this topic, please get in touch with Juliette Howarth, Nick Lee, Sam Bailey or your usual Kilburn & Strode advisor.