Therapeutics & Biomarkers

The Therapeutics & Biomarkers team at the Stanley Center is working to discover innovative therapeutics that will benefit individuals with severe psychiatric illnesses such as schizophrenia and bipolar disorder, as well as biomarkers needed to develop those treatments and to match affected individuals with the right interventions. Efforts to identify the most promising targets for new therapeutics and to discover biomarkers are grounded in emerging insights into disease mechanisms made possible by advances in psychiatric genetics and neurobiology. Many of the studies that inform the efforts of the Therapeutics & Biomarkers team involve research going on in Stanley Center Human Genetics and Neurobiology programs. Our strategy involves:

1. Nominating therapeutic targets, primarily based on our growing understanding of disease mechanisms informed by results from genetics and follow-on neurobiological studies
2. Exploring and validating therapeutic targets in human iPSCs, postmortem brain and animal models
3. Screening for and discovering small molecule compounds that can modulate target or target pathways in vitro and in vivo
4. Conducting proof-of-concept efficacy experiments in animal models
5. Discovering pharmacodynamic (PD) biomarkers to aid drug discovery, as well as biomarkers to improve disease diagnosis, stratify affected individuals within currently heterogeneous diagnostic classes, permit monitoring of disease progression, and provide objective evidence of therapeutic response

Drug Discovery

Drug discovery projects are focused on small molecule compounds for specific targets with the goal of achieving preclinical proof-of-concept for the therapeutic hypothesis. In collaboration with CDoT at Broad and industry partners, we identify and validate potential targets for drug intervention, screen for and optimize small molecule compounds that can modulate the activity of the target or target pathway(s) in therapeutically meaningful directions in vitro and in vivo, and perform proof-of-concept efficacy assays in animal and cellular models.

Additional efforts focused on neural channelopathies and depression mechanisms are also underway.

Biomarker Discovery

In tandem with small molecule projects, we research pharmacodynamic (PD) biomarkers that can be used to measure target engagement of the candidate therapeutic compounds in cells and animal models. We also leverage cellular and animal models as well as human molecular datasets to nominate candidate diagnostic or stratification biomarkers that could be used to identify individuals affected by schizophrenia for whom particular therapeutic approaches are more likely to be efficacious.

To discover quantitative fluid biomarkers needed for clinical development, we sponsor and direct the Schizophrenia Spectrum Biomarkers Consortium (SSBC), a multi-site effort that is building a repository containing biological samples generously donated from individuals affected by schizophrenia spectrum disorders and matched unaffected individuals. Longitudinally collected phenotypes (i.e. clinical symptoms, social functioning, cognitive status, structural and resting state MRI data) as well as genotypic data are also being collected. The banked biological samples include cerebrospinal fluid (CSF), blood serum and plasma, and peripheral blood mononuclear cells (PBMCs) that will permit the generation of induced pluripotent stem cell (iPSC) lines.

Another large focus is our Global Research Initiative on Neurophysiology of Schizophrenia (GRINS) program which is assessing translational electroencephalography (EEG) biomarkers in a large sample of individuals affected by, or at risk for, schizophrenia and matched unaffected individuals. A complementary effort involves the assessment of EEG biomarkers in animal models of psychiatric disease risk.