Gene Delivery Systems Designed for Cells in the Brain and Spinal Cord
The breakthrough could enable targeted therapies for many neurological disorders.
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Research teams funded by the National Institutes of Health (NIH) have developed a set of gene delivery tools designed to target specific cell types in the human brain and spinal cord.
These delivery systems represent an advance toward gene therapies that could selectively modify brain activity with high precision, compared to current approaches which only seek to manage symptoms.
The findings appear in eight papers published across journals including Neuron, Cell, Cell Reports, Cell Genomics and Cell Reports Methods.
Targeted gene delivery for neural cell types
The new gene delivery platform uses modified adeno-associated viruses (AAVs) to transport genetic material into targeted brain and spinal cord cells. This method enables researchers to study neural circuits across different species without the need for genetically engineered animals. For example, the systems can illuminate the fine structures of neurons with fluorescent proteins or modulate neural circuits involved in behavior and cognition by activating or silencing specific cells.
Adeno-associated virus (AAV)
AAV is a small virus used as a vector to deliver genetic material into cells. It is considered safe and effective for gene therapy because it does not cause disease in humans and can infect both dividing and non-dividing cells.
The newly published toolkit includes dozens of delivery systems that selectively reach key brain cell populations – such as excitatory neurons, inhibitory interneurons, blood vessel cells and the spinal cord neurons involved in body movement, which are often affected in neurological diseases including amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy.
“Imagine this new platform as a delivery truck dropping off specialized genetic packages in specific cell neighborhoods in the brain and spinal cord,” said John Ngai, Director of the NIH’s Brain Research Through Advancing Innovative Neurotechnologies® Initiative, or The BRAIN Initiative®. “With these delivery systems, we can now access and manipulate specific cells in the brain and spinal cord – access that was not possible before at this scale.”
Accelerating research on brain disorders
Complementing the delivery tools, the toolkit also includes computer programs powered by artificial intelligence (AI) that identify genetic "light switches" (also known enhancers) that regulate gene expression in particular brain cell types. These AI-driven programs analyze data from multiple species, reducing the time scientists spend locating these switches.
Collectively, the researchers hope that by allowing precise access to specific cell types in areas like the prefrontal cortex, this collection of tools will facilitate detailed studies of the individual cells and neural communication pathways that are known to be disrupted in conditions such as seizure disorders, ALS, Parkinson’s disease, Alzheimer’s disease, Huntington’s disease and various other neuropsychiatric disorders.
Availability and impact
Some AAV-based gene therapies are already approved for clinical use. For instance, the 2016 approval of Zolgensma gene therapy for spinal muscular atrophy has improved outcomes for affected infants and young children. This new gene delivery toolkit could enable more targeted treatments that affect only the diseased cells in the brain, spinal cord or brain blood vessels.
The toolkit is now available through distribution centers, including Addgene, making it accessible to the global research community. The published papers are intended to offer researchers standard operating procedures and user guides for applying tools.
The work is supported by the NIH’s Brain Research Through Advancing Innovative Neurotechnologies® Initiative, or The BRAIN Initiative, which supports interdisciplinary efforts to develop innovative neurotechnologies that enhance understanding of brain function in health and disease.
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