The philanthropic $4.5 million grant will enable the team to screen new, re-purposed drug candidates and apply them to patient-derived brain organoids to delve deeply into the causes of bipolar disorder
By Benjamin Boettner
(Boston) — The Wyss Institute’s CircaVent project will be supported by Breakthrough Discoveries for thriving with Bipolar Disorder (BD2), which aims to advance scientific understanding of the causes underlying bipolar disorder (BD). The CircaVent project examines the molecular mechanisms of common bipolar interventions and the pathophysiology of bipolar disorder to provide better insight into current drugs, improve upon their use, and develop better alternatives.
BD2 was created by philanthropic investors and the Milken Institute as a commitment to the nearly 40 million people affected by BD worldwide, those close to them, and the people not yet diagnosed with the disorder. With an integrative, collaborative research program, BD2 aims to overcome the progress-hindering lack of understanding about the basic disease mechanisms of BD, as well as factors influencing clinical approaches and outcomes.
“We are excited to support the Wyss Institute’s CircaVent team through our Discovery Research program,” said Cara Altimus, Ph.D., managing director of BD² and senior director at the Milken Institute. “By investigating current and possible therapies and deepening our understanding of their fundamental mechanisms, this research has the potential to rapidly transform how bipolar disorder is treated, helping us in our mission to ensure that everyone with bipolar disorder thrives.”
BD, previously referred to as manic depressive disorder, is characterized by life-disrupting and sometimes life-threatening mood swings ranging from extreme highs (mania) to extreme lows (depression) which can vary by severity, frequency, and duration from person to person. The diverse features and individual variances of BD have complicated its study, and led to the view of BD rather being a collection of several conditions. Presently, lithium and antipsychotics are prescribed to patients as first-line treatments, but little is known about how exactly they affect BD. Although both types of drugs, in principle, can successfully treat BD, they are not effective in a sizable subpopulation of patients, and cause several physical and mental side-effects that often cause patients to discontinue their treatments. More effective and personalized treatments are thus an urgent unmet need.
“The enormous complexities surrounding BD have made conventional drug discovery efforts unattractive as the standard approach requires a defined, disease-causing target,” said Wyss Core Faculty member George Church, Ph.D. “With CircaVent’s highly integrated multidisciplinary approach and now the generous philanthropic support from BD2, we hope to address both, the lack of knowledge on how BD arises and manifests itself, as well as the lack of more precisely acting therapies.” Church is the lead of the Wyss Institute’s Synthetic Biology platform, and also a Professor of Genetics at Harvard Medical School and of Health Sciences and Technology at Harvard and MIT.
CircaVent’s multidisciplinary approach to BD bundles the expertise of three groups at the Wyss Institute. Along its discovery process, it uses computational methods developed by the group of Wyss Founding Director Donald Ingber, Ph.D. to predict drug compounds that are already approved by the FDA for the treatment of other disorders, and that in the project, induce differences in entire gene expression programs between individuals with BD and healthy individuals, rather than merely regulating one particular target molecule. These differences should in part resemble those caused by lithium or antipsychotic drugs, which are known to be therapeutic. In the next step, the team will test identified drug candidates in human brain organoids derived from individuals with BD and healthy individuals.
“Our team is honored to have been selected by the BD2 program and excited to carry on this important work with this generous support. The CircaVent platform takes a new and unique approach to investigating bipolar disorder that has the potential to increase our understanding of its molecular and neuronal causes as well as to discover new drug candidates,” said Jenny Tam, Ph.D., the lead-PI on the grant and a Principal Scientist at the Wyss Institute leading its Institute’s Synthetic Biology platform together with Church.
Previously, the CircaVent team, which is part of the Wyss Institute’s Synthetic Biology platform led by Church, using induced pluripotent stem cells (iPSCs) derived from BD patients, had advanced the creation of human brain organoids. Importantly, brain organoids from non-BD patients exhibit neuronal activities distinct from patients with BD. Among the techniques the researchers will use to investigate BD brain organoids is Light-Seq, a method pioneered in the group of Wyss Faculty member Peng Yin, Ph.D., which enables mapping of the full gene expression repertoire (transcriptomics) within intact tissues (spatial profiling), as well as cutting-edge protein analysis (proteomics) to assess changes in protein expression and activity. In addition, the team will test the predicted drug compounds to a mouse model of bipolar disorder and investigate whether they can affect circadian activity – nearly all patients with BD experience severe insomnia during depression episodes or reduced need for sleep during manic episodes. Once they have evaluated new potential treatments in these preclinical systems, the team will work with clinicians, including Andrew Nierenberg, M.D., Professor of Psychiatry at HMS, and Director of the Dauten Family Center for Bipolar Treatment Innovation at Massachusetts General Hospital, to bring promising treatments directly to patients.
Besides Tam, the CircaVent team’s work on the supported BD project is coordinated by co-PIs Katharina Meyer, Ph.D., a neuroscience expert, Bogdan Budnik, Ph.D., a proteomics expert, as well as Ninning Liu, Ph.D., who co-invented the Light-Seq technology. Additional critical expertise is contributed to the project by Mariana Garcia-Corral, Michael Lewandowski, Shad Morten, Ayush Noori, Vivi Dang, and Michelle Yue.