Director, Chemical Neurobiology Laboratory, Center for Genomic Medicine, Massachusetts General Hospital
Co-Director, Precision Therapeutics Unit, Massachusetts General Hospital
Scientific Director, Neurobiology, Center for the Neuroscience of Psychedelics, Massachusetts General Hospital
Senior Associate Member, Broad Institute of MIT & Harvard
Affiliated Faculty, Harvard Stem Cell Institute
Faculty Member, Harvard Chemical Biology PhD Program
Faculty Member, Harvard Biological & Biomedical Sciences PhD Program
Precision Therapeutics Unit
Psychiatric Genetics & Neurodevelopmental Unit
Precision Medicine for Central Nervous System Disorders.
The Haggarty Laboratory seeks to elucidate and modulate the molecular mechanisms underlying neuroplasticity, the brain’s ability to change and reorganize its structure, function, and connections in response to various experiences and learning, for the prevention and treatment of psychiatric and neurological disorders. Through pioneering studies leveraging patient-derived stem cell models in conjunction with chemical genomics and systems neuropharmacology, we seek to unravel complex human disease biology and develop innovative mechanism-based targeted therapeutics. In parallel to our research efforts, we are also dedicated to training the next generation of translational neuroscientists whose creativity and insight will revolutionize our understanding of brain health and realize the promise of precision medicine.
Mechanism-Based Targeted Therapeutic Development for Neurological and Psychiatric Disorders
To advance novel therapeutic development for nervous system disorders, we are interested in characterizing and targeting phenotypes incurred by disease-associated proteins in neurological (e.g., Tau, PGRN, TDP-43) and neuropsychiatric disorders (TCF4, CIC, TSC, FMR1). Select examples of active projects in our laboratory include:
- Targeting Tauopathy in Dementia
Neurodegeneration refers to the loss of neuronal function and viability of cells in the human brain. A shared feature among neurodegenerative disorders is the accumulation of aberrant and deleterious protein inclusions in the most affected brain regions. In the case of frontotemporal dementia (FTD) spectrum disorders, one of such proteins is tau, an abundant microtubule-associated protein involved in diverse aspects of neuronal structure and physiology. Tauopathies, including FTD, are still without effective treatment, with few tau-specific therapeutics entering clinical trials.
Given this need for novel therapeutic strategies, our goal has been to investigate the step-by-step progression and development of pathophysiology in order to identify the early molecular and cellular changes in iPSC-derived, patient-specific neurons that potentially represent the stages when therapeutics would be more effective before overt neuronal death. This system is also a powerful platform for testing small molecules, introducing the human context early in the drug discovery pipeline. To identify experimental therapeutics with disease-modifying therapeutic potential, we work with different series of small molecules that reduce tau burden and toxicity in these patient-derived neuronal cell models. Some of these experimental drugs include tau-targeted protein degraders (PROTACs, AUTACs), enhancers of the autophagy-lysosomal machinery, and modifiers of tau spreading and seeding.
- Targeting Progranulin-Deficient Dementia
Some of the most significant genetic risk factors for FTD outside of MAPT (Tau) are mutations in GRN, which encodes progranulin (PGRN). Near ubiquitously, these mutations cause haploinsufficiency of PGRN. Progranulin deficiency causes broad lysosomal dysfunction characterized by inclusion-filled lysosomes and increased expression of lysosomal proteins such as cathepsin D and LAMP1. Moreover, recent literature has characterized PGRN as a modulator of microglial activity, as PGRN-deficient microglia are pathological in their impaired ability to phagocytose extracellular debris as well as in their increased expression of complement genes. Our laboratory aims to further characterize the phenotypes incurred by PGRN haploinsufficiency in various iPSC-derived cell types, and to identify small molecules that can restore PGRN expression to wild-type levels. Current efforts towards this goal include utilizing a microglia-based PGRN luciferase reporter line for high-throughput screening efforts, as well as characterization (both cell-based and in murine models) of novel classes of epigenetic-targeting small molecules previously identified in the laboratory.
- Neurobiology of Pitt-Hopkins Syndrome & TCF4
Dysregulation of WNT/β-catenin signaling has been implicated in the etiology and pathophysiology of multiple neuropsychiatric and neurodegenerative disorders. For instance, loss-of-function mutations in CTNNB1, the gene that encodes β-catenin, have been identified in several individuals with intellectual disability, while disruptions to the psychiatric risk gene ankyrin 3 (ANK3) have been shown to interfere with microtubule dynamics through activation of signaling by GSK and the collapsing response mediator protein 2 (CRMP2). WNT signaling has also been shown to promote mRNA and protein expression of transcription factor 4 (TCF4), mutations in which are implicated in Pitt-Hopkins syndrome, schizophrenia, and autism spectrum disorders. For these reasons, our laboratory is interested in discovering and characterizing novel activators of the WNT/β-catenin signaling pathway. We have previously designed and validated a sensitive, high-throughput screening-compatible WNT/β-catenin reporter system in human neural progenitor cells derived from iPSCs. Utilizing this screening system, we were able to conduct a screen of over 300,000 compounds. After extensive follow-up and functional validation, we identified multiple novel chemotypes of WNT/β-catenin enhancers in neural progenitor cells, which we are now working to mechanistically characterize and evaluate in murine models.
- The Neuroscience of Psychedelics & Ethnopharmacology of Psychoactive
In collaboration with the Center for the Neuroscience of Psychedelics at MGH, the Haggarty Laboratory is investigating the ethnobotany and ethnopharmacology of psychoactive plant and fungal-derived natural products. Our laboratory’s interest in studying these natural products and their synthetic derivatives arises from their remarkable ability to serve as modulators of neuroplasticity, which may hold therapeutic potential in a wide range of neurological and psychiatric disorders. We are interested in uncovering the molecular, cellular, and network-level impact of these molecules on neuroplasticity while learning from and respecting the Indigenous Peoples and traditions that have utilized these compounds for centuries. To this end, our laboratory is actively working toward studies of various psychoactive molecules, including endogenously biosynthesized psychoactive molecules in mammalian cells along with other genetically encoded small molecules biosynthesized by psychoactive plants.