This week, we profile a recent publication in Cell Reports from John Mich (pictured, lower right), Boaz Levi (upper right),
Ed Lein (upper left), and Jonathan Ting (lower left) at the Allen Institute for Brain Science.
Can you provide a brief overview of your lab’s current research focus?
We are building adeno-associated virus (AAV)-based genetic tools for basic research and human gene therapy that utilize enhancers to target gene expression to specific brain cell populations or circuits. To that end, we first reveal cell population-specific enhancers that can be used in our AAV tools through single cell epigenetic analyses of human brain cells. We then construct AAVs using the selective enhancers to drive gene expression in discrete cell populations. Finally, we validate selective reporter transgene expression from these new AAVs in multiple species, and these well-validated new tools can be used by neuroscientists to study the properties of the targeted cell populations across species. We are also applying enhancer-based AAVs to generate circuit-selective gene therapies we hope will provide more safe and effective treatments for neurological diseases.
What is the significance of the findings in this publication?
Our recent publications in Cell Reports and Neuron (co-submitted publication) demonstrate that we can precisely drive gene expression in specific types of brain cells. In our Cell Reports paper, we show that our AAV-based genetic tools can drive gene expression in the same distinct brain cell populations across species including mouse, non-human primate, and human. We are confident this strategy is extensible to most cell types, and our paper presents a blueprint that could be followed to build AAV-based genetic tools to target neural circuitry throughout the brain, or even to cell types in other organs. Our work provides a fundamental first step to bringing precision genetic experimentation to vertebrate species beyond the mouse and is a critical advance for the generation of circuit-selective precision gene therapies.
What are the next steps for this research?
Our publications in Cell Reports and Neuron are the first installments of brain cell-selective vectors and we only show selectivity for a few varieties of neurons. But single-cell molecular profiling studies at the Allen Institute for Brain Science and elsewhere are revealing many different types of cells throughout the brain, with each brain region exhibiting a unique taxonomy. We are currently leveraging these recent findings by generating AAV tools to target a wide variety of cell types and circuits across multiple species, expanding the collection of precision viral tools that can be applied to basic neuroscience research. Last, we are expanding our efforts to apply our vectors to AAV-based gene therapies to generate more precise therapeutics for neurological disorders.
This work was funded by:
We wish to thank the Allen Institute for Brain Science founder, Paul G. Allen, for his vision, encouragement, and support. This work is supported by NIH BRAIN Initiative award 1RF1MH114126-01 from the National Institute of Mental Health; National Institute on Drug Abuse award 1R01DA036909-01; the Nancy and Buster Alvord Endowment to C. Dirk Keene; and National Eye Institute award 1R01EY030441-01. This project was also supported in part by NIH grant P51OD010425 from the Office of Research Infrastructure Programs (ORIP) and grant UL1TR000423 from the National Center for Advancing Translational Sciences (NCATS). The contents of this study are solely the responsibility of the authors and do not necessarily represent the official view of NIH, ORIP, NCATS, the Institute of Translational Health Sciences, or the University of Washington National Primate Research Center.
