Scientists have discovered and amplified an evolved adeno-associated virus (AAV) to target and deliver gene therapy to retinal cells in mice. This discovery could lead to less invasive and more precise gene therapies for retinal degeneration diseases such as retinoschisis and Lebers congenital amaurosis, as well as disease in other organs that normally couldnt be treated with gene therapy because of the lack of tissue specific drug delivery systems.

This study, which was published in Science Translational Medicine and reported by TheScientist.com, is still in animal trials but has already been praised because of its potential to improve the outcome of gene therapy as well as to expand the use of gene therapy to other diseases.

For disease with genetic causes, gene therapy can be very effective because it treats the root of the problem, defective of missing genes. But one of the biggest problems with gene therapy is the delivery system: our bodies naturally digest DNA or RNA, and oftentimes the gene used for treatment breaks down before it reaches the target cells or tissues.

AAV vectors or delivery systems are very effective because it takes advantage of the virus life cycle. Most of us are aware that when viruses infect cells, as in the case of the common cold or even HIV, they destroy the cells in the process of creating more copies.

But some viruses dont destroy the cells they infect. Instead, they leave behind genes and insert them in the host DNA. Some viruses that cause cancer make use of this mechanism in order to shut down a cells natural apoptotic or self-destruct mechanism, causing the cells to grow uncontrollably and develop into cancer. Viruses like AAV often leave harmless genes and can even be manipulated to insert useful or therapeutic genes, making them great drug delivery systems.

But the problem with AAV is it often prefers to infect lung cells, making them hard to use for diseases that target other organs.

What Prof David Shaffer, research lead, and his team at the University of California in Berkley did was to isolate and propagate a version of the AAV virus that could infect other cells, in this case, retinal cells. AAV is a respiratory virus and so it evolved to infect lung epithelial cells, explained Schaffer to TheScientist.com. It never evolved to penetrate deep into tissue.

To test if it would be possible for AAV to evolve, they first injected regular AAV into the vitreous of the mouse eyes and a week later harvested cells from deep within the retina. As expected, most of the AAV didnt infect the retinal cells but a small portion eventually evolved and became capable of infecting photoreceptor cells. They then harvested these virus particles, repackaged them, and reinfected into another mouses eye. They did this six times in order to harvest enough virus variants to study and test, which they identified variant 7m8.

They then tested the effectiveness of this variant as a gene therapy vector by testing on mouse models with retinoschisis and Lebers congenital amaurosis. Both diseases are caused by missing genes, which made them ideal candidates for gene therapy through simple gene replacement. Those treated with the new AAV variant showed improved retinal function while those who were treated with regular AAV did not.

Lastly, they tested the variant on a macaque eye to see the variant would perform just as well in primates. Primates, which includes humans, have thicker retinas and the researchers had concerns that the AAV vector may not be able to penetrate deep enough into the retinal cells. The designed the AAV vector to express a fluorescent protein when it infects retinal cells and their results showed that the vector was able to target the photoreceptors up to the thinnest part of the retina or the fovea.

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Mutant virus used to treat blindness

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