Novel viral vectors deliver useful cargo to neurons throughout the brain and body.

Viruses have evolved to be highly effective vehicles for delivering genes into cells.  Such vectors have become critical tools for delivering genes to treat disease or to label neurons. Because viral vectors have been stripped of their own genes and, thereby, of 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 state that both vectors are customizable and could potentially be used as part of a gene therapy to treat neurodegenerative disorders that affect the entire central nervous system, such as Huntington’s disease, or to help map or modulate neuronal circuits and understand how they change during disease.  The study is published in the journal Nature Neuroscience.

Previous studies show that 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 AAV developed in 2016, engineering the virus’s shell, or capsid, to allow 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, which is able to transduce peripheral neurons.

The current study shows that the new AAV vectors can deliver cargo to neurons in the peripheral and central nervous system, as well as deliver genes that code for colourful fluorescent proteins to label cells.  In this labelling process, multiple AAVs, each carrying a distinct colour, are mixed together and injected into the bloodstream. Results show that when they reach their target neurons, each neuron receives a unique combination of colors, thereby giving it a visually distinct hue which makes it easier for the researchers to distinguish its fine details from those of its neighbours.

The team state that they also devised a technique to control the number of neurons labeled, which allows identification of individual neuron shapes and their connecting fibers through intact tissues.  They go on to add that the one of the most exciting implication is that their tools, when paired with appropriate activity modulator genes, could enable non-invasive deep brain modulation for the treatment of neurological diseases such as Parkinson’s disease.

The team surmise that they have developed two new variants of a vector based on an adeno-associated virus (AAV), one which can efficiently ferry genetic cargo past the blood-brain barrier; and another that is efficiently picked up by peripheral neurons residing outside the brain and spinal cord.  For the future, the researchers state that 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.

Source: Caltech

ft Novel viral vectors deliver useful cargo to neurons throughout the brain and body - neuroinnovations

The researchers used the engineered viral vector AAV-PHP.S to label neurons lining the digestive tract with a cocktail of three distinct fluorescent proteins. Due to the stochastic uptake of viruses encoding either a blue, green or red fluorescent protein, cells are labeled with a wide range of hues. This multicolor approach can be used to differentiate neighboring neurons for morphology and tracing studies. Credit: Chan et al., Gradinaru Lab; Nature Neuroscience.

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