Brain-enriched voltage-gated calcium channel isoforms: novel, genetically informed, therapeutic targets for psychiatric disorders

The last few years have seen substantial progress in our understanding of the genetic basis of psychiatric illnesses such as schizophrenia and bipolar disorder (also known as manic depression). It is hoped, and often claimed, that this knowledge will lead to insights into the biology of these illnesses and new therapies. However, concrete examples of this argument are lacking. This research will begin to examine how we can move from genetic insights to new therapies by focussing on arguably the most promising set of molecules arising from the recent genetic studies: the voltage gated calcium channels (VGCCs).

Calcium is an important signalling molecule and plays a key role in brain function. There is long-standing evidence that patients with bipolar disorder have abnormalities in calcium function. Recent genetic studies suggest that these abnormalities may be caused, in part, by alterations in the function of the VGCCs. These channels make attractive drug targets for treating bipolar disorder and other psychiatric disorders in which these channels are implicated. However, many different types of VGCCs are produced from a limited number of VGCC genes, and there is a lack of information about the precise types of VGCCs that are present in human brain, and how these channels are changed in psychiatric disorders and in those at higher genetic risk for these illnesses. Neither do we know how the critical brain VGCCs differ from those found elsewhere in the body. This grant will directly answer these three questions by identifying the VGCCs present and enriched in human brain, compared to other body tissues, and investigating how they are changed in association with genetic risk for psychiatric disorders, and in the diseases themselves. These studies will take advantage of a wealth of data that has already been collected, some of which we have unique access to. We will combine analysis of these existing datasets with cutting-edge experimental studies. Crucially, both our analyses and experiments will use human brain tissue. This is essential, because the number of different molecules that a single gene produces is much higher in humans than in others species, particularly in human brain, compared with other types of body tissue. Most of the studies that have investigated the types of VGCCs present in brain vs other tissues have either used animal tissue, or have looked at only a few people, which is unlikely to be sufficient to address this question. Indeed, our preliminary studies already demonstrate that much remains unknown about the types of VGCCs that are present in the human brain.

The research described here will help us to understand the key brain-enriched types of VGCC to target to improve the treatment of psychiatric illnesses, as well as investigating how genetic variation in the VGCCs increases risk for developing them. More broadly, they will also provide a test of how we can begin to move from genetic findings to new treatments.

Robust genetic risk factors have been identified for psychiatric disorders. However, the pathway from gene to pathophysiological insight to novel treatment is yet to be elucidated. The research described here provides the critical first steps in this essential pipeline for arguably the most promising protein family: the voltage-gated calcium channels (VGCCs).

Calcium dysfunction has long been implicated in psychiatric illness. Genetic findings suggest a causal role for the VGCCs. Given their disease associations, clear neurobiological function and established 'druggability', they are attractive psychiatric therapeutic targets. However, progress is hampered by a lack of information about the specific VGCC isoforms present in human brain and which of these mediate disease risk. As well as being important to understand links between VGCCs and disease, this information is essential for drug development, since VGCCs also play key roles in the cardiovascular system.

This research combines computational and experimental studies to address these unknowns focussing, crucially, on human brain tissue. We will use our unique access to RNASeq data from the largest and highest-quality brain series available from healthy controls and psychiatric patients, to determine the brain transcript profile of VGCCs, and will contrast this with that of peripheral tissues, using publicly available multi-tissue RNASeq data. We will use cutting-edge methods - combining CaptureSeq and long-range PCR with long-read sequencing - to identify all VGCC isoforms, and to disambiguate the full-length transcripts (essential given their large size). We will then test for associations between VGCC isoforms and genetic risk loci, as well as disease status.

In addition to the academic benefits (noted in the 'Academic Beneficiaries' section), this research will be of significant direct and indirect impacts for drug development in the field, of value to industry and ultimately to the public.

1) As outlined in the Case for Support, VGCCs are an attractive therapeutic target for bipolar disorder. However, the potential for non-selective effects of VGCC drugs is a significant barrier to progress. One of the key aims of the proposed research is to identify human, brain-enriched isoforms that should prove more selective targets for psychiatric indications (and our pilot data and the available literature already suggest that such isoforms exist). Once identified, we will work with our partners both within academia (e.g. the Structural Genomics Consortium and the Target Discovery Institutes) and industry to advance the therapeutic candidacy of these isoforms. Notably, given the lack of success in developing drugs for psychiatric disorders within the traditional pharmaceutic company R&D model, the boundaries between academia and industry are becoming increasingly blurred: several of these academic partners, in fact collaborate extensively with industrial consortia and the data that result from them are made freely-available to the scientific community.

2) In addition to the direct relevance of this research for drug development, the proposed work will, en passant, provide high quality training to post-doctoral researcher in cutting edge bioinformatics analysis techniques. This is of significant value, given the increasing wealth of large-scale data being generated (notably by consortia increasingly including both academic and industrial partners).

3) In the course of our research we have found that the neurobiological mechanisms of psychiatric disorders and their potential for improving treatment are of significant interest to the general public. The proposed research is therefore likely to provide opportunities to engage with the public to promote the public understanding of science.