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Broad Plans Large Sequencing Study to ID Personalized Drug Candidates for Psychiatric Disorders


Originally published July 28.

NEW YORK (GenomeWeb) – After announcing that it has been promised $650 million in support from philanthropist Ted Stanley, the Broad Institute's Stanley Center is now planning a large-scale sequencing study to attempt to identify new molecular drug targets in psychiatric disorders and begin screening compounds that could be developed into personalized therapies for these diseases.

While many patients with schizophrenia, bipolar disorder, and other psychiatric conditions respond to available drugs, results can vary widely from patient to patient, and many individuals fail to benefit at all. For those who fail to respond to standard antipsychotic therapies, few alternatives exist.

The Broad team hopes that by exhausting the human genome for insight into the biological mechanisms of these diseases, it may be able to discover new drug targets and identify compounds that could become personalized therapies.

Initially opened with a financial gift from Stanley in 2007, the Broad’s Stanley Center has already made early progress in identifying genetic risk factors for schizophrenia and bipolar disorder. Last week researchers from Broad and other institutes participating in the Psychiatric Genetics Consortium published a GWAS analysis in Nature that identified more than 100 regions of the human genome associated with schizophrenia.

The study found that many of the associated genes were expressed in the brain, providing biologic plausibility for their role in psychiatric dysfunction. The researchers also reported that the findings suggest some novel biological and etiological insight. For example, apart from the brain, some genes in the study were also expressed in immune-associated tissues, providing support for a speculated link between the immune system and schizophrenia.

According to Steven Hyman, director of the Stanley Center, the insights from this study, along with other discoveries being made by the Broad and its collaborators, have given the ambitious project its first promising toe holds.

"We have turned with this paper what was a scientifically forbidding and featureless landscape into a … glimmer of hope," he said during a webcast presentation announcing the new bequest from Stanley.

Because knowledge about psychiatric disorders has been so limited and drug development has been effectively stalled since the 1960s, Hyman said the opportunity for improved understanding of the disorders and the identification of new drug targets is large.

"These disorders are leading causes of disability worldwide," Hyman said. "If we can get from here to there, there will be real markets and opportunities," he added.

Moving forward under its newly promised funding, the center now plans to delve deeper than previous analyses. Rather than relying on genotyping and GWAS, the Stanley center team plans to sequence the exomes, and in some cases whole genomes, of more than 100,000 patients over the next few years.

Hyman shared more details of the group's plans for the funding with PGx Reporter this week.

He said the team has a large number of samples in its freezer – about 200,000 from patients with schizophrenia, bipolar disorder, autism, and ADHD – collected with the help of international collaborators. The researchers plan to use mostly exome sequencing, but also some whole-genome sequencing, to attempt to identify genetic alterations associated with risk for these disorders.

According to Hyman, the team has not yet finalized exactly how many of these samples to sequence or what proportion will be analyzed with exome versus whole-genome sequencing, but it definitely plans to do both.

A challenge for the project is that most of these banked samples are biased toward Northern European populations. In light of this, the team is working to collect samples from other populations to add to the study.

"We already have enough samples to keep us busy, but we very much want to expand to other populations for both scientific and global equity reasons," Hyman said. "We don't know ultimately how these diseases will stratify and we certainly don't want to produce medicines only for people who look like us, so it's very important in this phase where we are focused on genetic analysis that we get it right."

In addition to genome sequencing, Hyman said the team would also be exploring transcriptome sequencing and unbiased epigenetics analysis.

As new risk markers are identified, the group will then attempt to pick out the most promising using neurons differentiated from lab-grown stem cells, and then move the most interesting subset of candidates into animal and other models.

In these, the group will be able to test compounds and chemicals designed to target each particular disease-associated molecular lesion or biological pathway.

According to the Broad, the project will draw on the institute's Therapeutics Platform to develop compounds that modulate key molecular and biologic pathways that they will investigate as potential targeted psychiatric drugs.

Particularly difficult in applying these analyses to psychiatric disease, Hyman said, is that fact that there is no way to know for sure that phenotypes seen in model or in vitro systems actually reflect the experiences of human patients.

"Selecting those phenotypes you want to screen against because they really matter for humans, it's going to be hard," he said. The group hopes it will be able to experiment with different phenotyping techniques and animal systems to try to overcome this issue.

Ahead of a deeper understanding of the molecular underpinnings of schizophrenia and other psychiatric conditions and the development of a new class of therapies, companies are already marketing tests using pharmacogenomic markers to predict patients' responses to currently available drugs.

Assurex recently saw its GeneSight Psychotropic test approved by the US Department of Veterans Affairs for use in personalizing treatment for veterans. GeneSight analyzes a panel of pharmacokinetic genes from the CYP450 family and pharmacodynamic genes implicated in the serotonin system that have been shown in studies to affect a person's response to antidepressant and antipsychotic treatments.

Another company, Genomind, markets a test that analyzes pharmacokinetic CYP450 genes, including CYP2D6 and CYP2C19, and pharmacodynamic genes SLC6A4, CACNA1C, DRD2, COMT, and MTHFR to predict which psychiatric drugs a patient is likely to respond to.

Hyman said that the Broad group is also interested in potentially exploring genomic underpinnings of patients' response to available drugs, but that teasing these types of links out of their own analyses would be difficult since most patients in their cohort have been treated with multiple therapies over time.

Hyman said the group has had some discussion with potential partners from the pharmaceutical industry about sharing data on responders and non-responders, but as of yet they have not made any agreements.