Scientists create next generation of tools in battle against brain disease
The findings contained in eight studies could lead to targeted gene therapies for brain disorders.
Researchers from around 29 universities and institutions across North America have teamed up to create a large, versatile, and effective arsenal of new biological tools that will play a critical role in the battle against brain disease. The tools are known as “enhancer AAV vectors”. The team has successfully created over 1000 of them, and each consist of:
- a harmless adeno-associated virus (or AAV) that acts like a shuttle capable of transporting specially designed DNA into the cell;
- a segment of DNA (an enhancer) that acts like an “activation switch” to mark or trigger a change in how the cell functions.
The cell-type specific targeting capability of these new genetic tools opens the door to targeted gene therapies that can correct genetic defects in specific cells that contribute to disease without affecting surrounding cells and adding unwanted side effects. Scientists now have new tools to help design the next generation of drugs to help treat brain disorders. They also now have unprecedented experimental access to brain cells that were difficult to study.
“Gaining access to a variety of cell types is simply put a ‘game-changer’ in understanding the brain and developing therapies for human neurological disorders,” said Gordon Fishell, an institute member at the ӳý, professor of neurobiology at Harvard Medical School, and a senior author of . “The enthusiasm in which these tools have been both jointly tested and adopted by the broader community speaks to what we can achieve in science when we work together.”
“There is an overall principle that diseases usually arise from flaws in specific cell types, not the whole organism. For example, epilepsy is a nervous system disease that is actually a disease of specific neurons in the nervous system,” said Bosiljka Tasic, director of molecular genetics at the Allen Institute and author of one of the studies. “If you want to fix those neurons, you can try to access only those neurons. The key is this cell-type specific access for understanding and perturbing brain cells to figure out their function, and for correcting and fixing the defective parts of these cells.”
This type of cell-type targeting has never been demonstrated at this scale and effectiveness before. The findings were published in eight studies in the Cell Press family of journals (Neuron, Cell, Cell Reports Method, Cell Reports, Cell Genomics). Collaborators include the Allen Institute; ӳý; Harvard Medical School; Duke University; University of California, Irvine; University of California, Berkeley; University of Pittsburg; Carnegie Mellon; Stanford, University of Washington, and Addgene.
The work is part of the , a transformative project within the National Institutes of Health’s Brain Research Through Advancing Innovative Neurotechnologies® Initiative, or ®. Its central goal is to develop, scale, and distribute a comprehensive toolkit (an "armamentarium") of molecular and genetic tools that can interface with specific brain cells.
“Homing in on the right cells—in the right way and at the right time—is the future of precision brain medicine,” said John Ngai, director of the NIH BRAIN Initiative. “These tools move us closer to that future, while also expanding what we know about the brain’s cells and circuits today.
Key findings
- Researchers successfully designed genomic tools for an incredible diversity of brain cell types, including for both cortex (.; .) and striatum () brain regions, as well as the spinal cord (.).
- The team will be safer and more effective for debilitating brain disorders. Researchers recently demonstrated the benefit of cell-type targeting in a .
- The new tools were very effective at targeting specific brain cells and allowing scientists to successfully change cell activity and animal behavior in a predictable way. In , scientists successfully targeted and labeled a rare cell that regulates sleep, opening the door to new cell type-specific treatments for sleeping disorders.
“The rapidly growing collection of brain cell type enhancer AAV vectors with unprecedented strength and specificity of labeling hold great promise to enable new avenues for brain cell type targeting and perturbation in diverse mammalian model organisms and potentially humans,” said Jonathan Ting, one of the study authors and associate investigator at the Allen Institute.
The tools and data in the studies are freely available on the Allen Institute’s and through . These materials will serve as a valuable, catalytic resource for the global scientific community working to find new treatments and therapies for brain disease.
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