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Viruses Altered to Boost Gene Therapy Delivery



13 Dec. 2019. Researchers in Sweden developed a process to improve the targeting of benign viruses for delivering gene therapies to the brain. Neuroscientists from Lund University describe their techniques in the 9 December issue of the Proceedings of the National Academy of Sciences.

A team from the molecular neuromodulation lab of Tomas Björklund at Lund University is seeking to improve the ability of viruses to better identify their targets among cells in the brain for delivering gene therapies. Many gene therapies, including gene-editing techniques such as Crispr, deliver healthy or modified genes with adeno-associated viruses. The adeno-associated virus is a benign and naturally occurring microbe that infects cells, but does not integrate with the cell’s genome or cause disease, other than at most mild reactions.

In their natural state, however, adeno-associated viruses or AAVs are imperfect delivery vehicles for gene therapies. One drawback is the ability to find the precise cells to deliver the modified genes, which reduces their efficacy and may result in off-target adverse effects. That’s a key concern for neuroscientists developing treatments for conditions such as Parkinson’s disease, where therapies need to identify and deliver gene therapies to dopamine-producing neurons, or nerve cells.

To improve this targeting ability, Björklund and colleagues devised a process for altering the protein shell on the virus known as the capsid to better reflect the molecular make-up of the cells needing the treatment. The researchers call their technique “Brave,” short for barcoded rational AAV vector evolution. The Brave process modifies the virus’s capsid to add a peptide, or short chain of amino acids known to interact with neurons to the capsid surface. The process, aided by a statistical model, also adds a unique molecular identifier — i.e., bar code — derived from RNA representing the genome sequence for repair.

With this process, the Lund team prepared a library of nearly 4 million combinations of peptides and bar codes that the authors say can map to specific binding sequences of proteins, and thus offers precise targeting for gene therapies with adeno-associated viruses. The researchers first validated their modified viruses to deliver gene therapies to dopamine-producing neurons derived from stem cells in lab cultures, then in lab rats transplanted with human dopamine-producing neurons, as well as nerve cells producing the toxic tau proteins and amygdala neurons associated with anxiety.

“Thanks to this technology” says Björklund in a university statement, “we can study millions of new virus variants in cell culture and animal models simultaneously. From this, we can subsequently create a computer simulation that constructs the most suitable virus shell for the chosen application, in this case, the dopamine-producing nerve cells for the treatment of Parkinson’s disease.”

Björklund is a co-founder of Dyno Therapeutics, a start-up company in Cambridge, Massachusetts, synthesizing viral capsids for precise delivery of gene therapies. As reported last month in Science & Enterprise, researchers from Harvard’s Wyss Institute and Dyno Therapeutics developed synthetic viruses to deliver gene therapies to the spleen, liver, kidneys, heart, and lungs in lab mice.

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