New knowledge, approaches, and technologies being used at the Earlham Institute and the University of Oxford may bring us a step closer to a safe and effective treatment for serious mental health conditions.
During the 1960s, doctors welcomed a new class of drugs for the treatment of several serious cardiovascular conditions.
Dihydropyridines, also known as calcium channel blockers, help to relax blood vessels and lower blood pressure. They are effective in treating hypertension, angina, and some abnormal heart rhythms.
But, over time, cardiologists noticed an unexpected trend in patients who also had serious neuropsychiatric disorders including schizophrenia or major depressive disorder. When they were prescribed dihydropyridines, lower risks for neuropsychiatric events were also observed.
It is now accepted that these drugs - especially those that can cross the blood-brain barrier - can have an impact on the brain. Using them could provide a breakthrough in treating severe mental illnesses.
However, calcium channels are the primary target of these drugs. These channels are widespread across the human body - in our heart, the smooth muscles of the intestine, the retina, the inner hair cells of our ears, and the neurons of our brains.
The ubiquity of calcium channels makes system-wide treatments ineffective - and potentially dangerous. Targeted therapies are needed.
New knowledge, approaches, and technologies being used at the Earlham Institute and the University of Oxford may bring us a step closer to a safe and effective treatment for these mental health conditions.
[This gene] is expressed in the heart and lungs, as well as other smooth muscles. This means, at the moment, we can’t give it to people with schizophrenia - or other mental health patients - at levels which would help them, because of the risk of causing severe secondary effects.
The CACNA1C gene, found on chromosome 12, is one of the major candidate genes associated with risk for neuropsychiatric disorders.
Crucially, CACNA1C gene products respond to medication - the gene has already been found to be susceptible to dihydropyridines, making it an ideal target for treating these disorders.
But it expresses throughout the body, generating dozens of products, including some of which change between organs or over the course of a life.
“Everything in our bodies – every excitable cell – expresses this gene family,” explains Dr Wilfried Haerty, group leader at the Earlham Institute. “It is expressed in the heart and lungs, as well as other smooth muscles.
“This means, at the moment, we can’t give it to people with schizophrenia - or other mental health patients - at levels which would help them, because of the risk of causing severe secondary effects.”
A single gene can express different products - isoforms - depending on where the gene is located in the body and when during development or ageing it is expressed. This can be a result of a different binding site or transcription factor being involved.
Different isoforms could be used to narrow down the physical target of medication. If an isoform only occurs in one organ or system, targeting that gene product should leave the rest of the body unaffected.
“We need to find a way of activating this drug in the brain only,” explains Dr Haerty. “The way this can be done is via different isoforms expressed by the gene.”
To do this, Dr Haerty has been combining approaches in collaboration with researchers at Oxford University.
He has been analysing sequencing data generated by collaborators at the Department of Psychiatry in the University of Oxford, as well as conducting bioinformatic analyses of publicly available data on CACNA1C expression across human tissues.
We need to find a way of activating this drug in the brain only. The way this can be done is via different isoforms expressed by the gene.
Schizophrenia presents in varying ways, but is characterised by an impaired understanding of what is real. It affects around 24 million people worldwide and causes a wide range of disabling symptoms.
People living with schizophrenia are two to three times more likely to die early than the general population, and they often suffer stigma, human rights violations, and mistreatment.
No single cause has been identified for schizophrenia. It is currently believed to result from complex interplay between multiple genes and the external environment.
Dr Haerty’s plans for future work - in close collaboration with researchers at the University of Oxford - include proteomics for CACNA1C, isolating the gene’s RNA expression, and predicting which RNA transcripts are expressed as specific isoforms.
Research so far has been funded by the MRC, BBSRC, and the Psychiatry Consortium - an international £4 million collaboration between seven global pharmaceutical companies and two leading research charities, overseen by the Medicines Discovery Catapult.
