Enterprise Innovation interviewed rising innovator Dr. Anna Orr. In this conversation, Dr. Orr shares the translational research in neuroscience that is being conducted in her lab as well as how early-career faculty can leverage resources offered by the Weill Cornell Medicine innovation ecosystem to advance their discoveries.
Dr. Orr is the Nan and Stephen Swid Assistant Professor of Frontotemporal Dementia Research and an assistant professor of neuroscience in the Feil Family Brain and Mind Research Institute. She received her doctorate in neuroscience from Emory University, where she conducted research with Dr. Stephen Traynelis on mechanisms of glial cell motility, responses to brain injury and changes in receptor signaling in neuroinflammation. Dr. Orr completed her postdoctoral training under the guidance of Dr. Lennart Mucke at the Gladstone Institutes of Neurological Disease and University of California San Francisco. There, Dr. Orr led studies showing for the first time that receptor activities in glial cells called astrocytes regulate memory and can contribute to cognitive deficits in dementia.
In addition to generous support from the Daedalus Fund for Innovation at Enterprise Innovation, research in the Orr lab has also been supported by the National Institute on Aging, National Institute of Neurological Disorders and Stroke, Alzheimer’s Drug Discovery Foundation, the Association for Frontotemporal Degeneration, Alzheimer's Association, and other organizations.
What areas of neuroscience research are currently ongoing in the Orr lab? What are the potential translational applications of your research for patients?
We are broadly interested in unraveling the properties and functions of brain cells called astrocytes and their pathobiological roles in neurodegenerative diseases, including Alzheimer’s disease and frontotemporal dementia. Astrocytes, like other glial cells, are critical to brain function, but they are poorly understood. Among our diverse projects, we are investigating the roles of astrocytic receptor signaling in cognitive function and behavior, how changes in mitochondrial production of reactive oxygen species (ROS) affect the cells and disease-related processes, and how the presence of abnormal clumps of proteins and other molecular alterations in astrocytes can cause aberrant neuroimmune responses and cognitive impairments. We use preclinical models and other techniques to understand the underlying biology of astrocytes and to conduct preclinical drug design and testing for potential therapeutic applications. Thus, we address basic and translational questions in neurobiology and aim to uncover new avenues for drug and biomarker development.
Alzheimer’s disease, frontotemporal dementia, and other neurodegenerative disorders are prevalent and multifactorial neurological conditions. These dementias represent the only top cause of death that cannot be effectively treated or prevented. Diversified therapeutic strategies are urgently needed to combat this growing public health crisis. Our research is tackling how aberrant glial signaling, neuroimmune dysregulation, and redox-related pathways affect brain function at cellular and behavioral levels, and which molecular targets in these interrelated cascades are amenable to therapeutic intervention. We are currently developing and testing novel site-specific inhibitors that target mitochondrial production of ROS, which promote aberrant redox pathways if left unchecked. These inhibitors may be a promising therapeutic approach due to their unique mechanism of action, disease-modifying properties, and long-term tolerability in animal models. We are also investigating differences in the effects of astrocytes across various brain regions and between sexes and whether targeting certain astrocyte pathways might be effective as preventative or therapeutic interventions for dementia.
What motivated you to start working with Enterprise Innovation?
In partnership with Dr. Adam Orr, who is also faculty in the Feil Family Brain and Mind Research Institute and co-runs the lab with me, we are investigating the roles of ROS released by mitochondria and whether precise blockers of these damaging factors can alleviate dementia-related pathogenesis. Increases in ROS are thought to underlie diverse pathological processes in aging and disease due to their detrimental effects on cell signaling, inflammatory responses, and cell homeostasis. However, current genetic and pharmacologic tools to block mitochondrial ROS typically affect metabolism and disrupt cellular redox, and therefore have limited clinical applications. Dr. Adam Orr previously discovered several classes of small molecules that selectively inhibit specific sources of ROS production in the mitochondria without disrupting metabolism and other processes. We have been testing these inhibitors in various experimental systems and uncovered that they have beneficial effects in models of disease.
Dr. Adam Orr (Provided)
These developments motivated us to consult with the team at Enterprise Innovation to file a utility patent, obtain guidance on potential partnerships and funding opportunities for further translational studies, and discuss strategies for effectively moving the project from bench to bedside.
How did the grant from Daedalus Fund for Innovation help advance the research in your lab?
We aim to develop selective mitochondrial modulators as therapeutics for dementia and other conditions with similar mechanisms. However, currently used modulators are not unique compositions of matter and require further optimization and development. We therefore applied for support from the Daedalus Fund for Innovation to work together with Dr. Subhash Sinha, a talented medicinal chemist in the Appel Alzheimer’s Disease Research Institute in the Feil Family Brain and Mind Research Institute at Weill Cornell Medicine, on designing, synthesizing, and testing next-generation modulators with possibly improved efficacy, clinical utility, and commercial opportunities. The year-long support from the Daedalus Fund enabled us to generate and test many new chemical structures and identify beneficial chemical modifications for further development. This valuable advance enabled us to file a compositions-of-matter patent and strengthen our IP position. Overall, the insights and chemical tools gained from these studies facilitated our drug discovery process and served as a useful and necessary step forward.
Do you have any advice to early-career faculty that want to explore the potential commercial applications of their research?
I have learned a great deal from my interactions with the team at Enterprise Innovation, who are all knowledgeable, supportive, and responsive to requests and questions. I would, therefore, advise new faculty to reach out to this team on a regular basis for strategic advice, funding and partnership opportunities, and other useful resources.
What do you see as the next big breakthrough in neuroscience?
I think that integration of whole-brain imaging and omics datasets, including redox proteomics, with multidimensional functional outcomes, such as cell signaling, circuit activities, behavioral patterns and disease outcomes, would greatly advance our understanding of neurobiology and brain disorders by providing a more holistic view of neural (dys)function and therapeutics. Perhaps this advance will be facilitated by recent developments in machine learning and artificial intelligence.