Researchers Find Better Way to Deliver Gene Therapy

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While gene therapy continues to be a promising area of medicine, a major drawback of this kind of treatment can spell failure for many patients enrolled in gene therapy clinical trials: Most people’s immune systems may destroy the viral carrier that is most often used to deliver healthy genes into sick cells.

A new study explains that scientists may have found a way around this problem.

Researchers used a laboratory technique called polymerase chain reaction (PCR) to alter genetic sequences of the outer coating, or capsid, of adeno-associated virus (AAV). AAV is a normally innocuous virus that is often used to deliver healthy genes to diseased tissues.

"We were able to make random changes throughout the entire genetic sequence of the AAV capsid,” said Brian Kaspar, a study co-author and an assistant professor of pediatrics at Ohio State University.

“And by doing that we generated more than a million different variations of this capsid, including mutations that the human immune system hopefully won’t recognize and therefore shouldn’t react against.”

The researchers describe their technique in the current issue of the journal Nature Biotechnology.

In gene therapy, physicians insert healthy genes into a person who has an unhealthy form of those genes. The hope is that these new, good genes will correct the problem. Viruses are currently the most common vehicle used to deliver genes into the body.

“Most clinical trials that test gene therapy use AAV because it is a virus that doesn’t make people sick,” said Kaspar, who is also an investigator with the Center for Gene Therapy at Columbus Children’s Research Institute.

While AAV doesn’t appear to have any adverse affect on health, researchers estimate that anywhere from 50 to 90 percent of people react to the AAV as if it were an intruder.

This has presented problems in some clinical trials where patients created antibodies that destroyed the virus, and decimating the virus also wipes out the healthy genes that it carries.

But Kaspar and his colleagues tapped into the evolutionary mechanisms that virus’ use to alter their capsids. Viruses can quickly change, or mutate, these outer shells in order to adapt to new environments or to infect different types of species.

The capsid surrounds a virus particle’s genetic material. When viruses infect cells, they use a cell’s machinery to copy their own genetic material.

Gene therapy is still in the experimental stages for a number of reasons. It has been difficult to find a delivery vehicle that won’t trigger a reaction by the immune system, and the vehicles that are available, such as AAV, may act differently on different tissues in the body.

Now that they have a massive library of AAV variations, Kaspar says it’s possible to fish out different capsid mutations based on the type of tissue or kind of disease that scientists want to treat. They can also conduct laboratory tests to determine which AAV capsid variations are able to avoid detection by the human immune system.

“We can control how AAV evolves and then select for the variations that perform whatever function we are interested in, such as evading the immune response that humans have naturally developed, or targeting a particular type of tissue,” Kaspar said.

He co-authored the study with lead author David Schaffer, Narendra Maheshri and James Koerber, all with the Helen Wills Neuroscience Institute at the University of California, Berkeley.

The work was funded in part by National Science Foundation graduate fellowships, Project A.L.S., the Whitaker Foundation and the ALS Association.

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