Viruses have evolved to be highly effective vehicles for delivering genes into cells, with these vectors becoming critical in delivering genes to treat disease or label neurons. As viral vectors have been stripped of their own genes and their ability to replicate, they are no longer infectious, therefore, achieving widespread gene delivery with the vectors is challenging. This is especially true for gene delivery to the brain, where viral vectors have to make their way past the blood-brain barrier, or to the peripheral nervous system where neurons are dispersed across the body. Now, a study from researchers at Caltech enables widespread gene delivery throughout the central and peripheral nervous systems. The team states both vectors are customizable and could potentially be used as part of a gene therapy to treat neurodegenerative disorders affecting the entire central nervous system, such as Huntington’s disease. The study is published in the journal Nature Neuroscience.
Previous studies have shown neurons outside of the central nervous system have many functions, from relaying sensory information to controlling organ function, however, some of these peripheral neural circuits are not yet well understood. The current study modifies the external surface of an Adeno-Associated Virus (AAV) by engineering the virus’s shell, allowing it to more efficiently deliver genes to cells in the brain and spinal cord following intravenous injection. The new virus is named AAV-PHP.eB, with an additional capsid variant called AAV-PHP.S, with the ability to transduce peripheral neurons.
The current study shows the new AAV vectors can deliver cargo to neurons in the peripheral and central nervous system, as well as deliver genes coding for colorful fluorescent proteins to label cells. In this labeling process, multiple AAVs, each carrying a distinct color, are mixed together and injected into the bloodstream. Results show when they reach their target neurons, each neuron receives a unique combination of colors, thereby giving it a visually distinct hue making it easier for the researchers to distinguish its details from those of its neighbors.
The team states they also devised a technique to control the number of neurons labeled, allowing the identification of individual neuron shapes and their connecting fibers through intact tissues. They go on to add one of the most exciting implications involves pairing the tools with the appropriate activity in modulator genes, providing the potential for the development of non-invasive deep brain modulation to treat neurological diseases such as Parkinson’s disease.
The team surmises they have developed two new variants of a vector-based on an AAV, one variant can ferry genetic cargo past the blood-brain barrier, whilst the other enables uptake by peripheral neurons residing outside the brain. For the future, the researchers state their new systemic viral vectors have many potential uses, from mapping circuits in the periphery and fast screening of gene regulatory elements, to genome editing with powerful tools such as CRISPR.
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