If you’ve ever accidentally set off your own home security system or car alarm, you know that while these systems can provide great protection, they have a hard time separating friend from foe.

Researchers in the field of gene therapy are facing a similar challenge in their quest to use modified viruses (known as viral vectors) to deliver healthy genes to patients with genetic disorders.

While the viruses that are used in these treatments have been modified so they will help patients instead of harming them, it’s hard to explain that to the body’s immune system, which functions as our in-house security force.

Finding ways to help viral vectors evade immune detection and improve the success rate of gene therapy treatments is the primary goal of Casey Maguire, PhD and his research team (Bence György, MD, PhD and Adri Volak, MS) at Massachusetts General Hospital.

Thanks to a discovery about a subset of viruses that are commonly used for gene therapy, Maguire may have found a way to get viral vectors past the well-meaning security guards of our immune system, and into the cells where they can help patients the most.

How gene therapy works

Genetic disorders are caused by mutations in the genetic code that often result in missing or malfunctioning proteins. Gene therapy seeks to treats patients with genetic disorders by giving them healthy genes to replace faulty ones.

There are several ways to deliver these genes, but the most successful method so far employs viral vectors—viruses that have been stripped of any potential harmful characteristics and further modified to express a gene of interest.

The viral vectors are injected into the patient (either intravenously or directly into the target site), where they can deliver their therapeutic genetic payload to host cells.

Adeno-associated viruses (AAVs), tiny viruses with a diameter of less than one-thousandth of a human hair, are one of the most popular vectors because they are not inherently harmful to humans, have an easily editable genome, and are naturally inclined to deliver DNA to cells that are impacted in a variety of genetic disorders. They have shown promising results in clinical trials for hemophilia and hereditary blindness.

A recent clinical trial using AAVs to treat a deadly neuromuscular disease called spinal muscular atrophy has vastly improved the life expectancy of babies with this disorder, who can die within six months of birth. So far all of the patients treated in the trial are 20 months old and have no complications from the disorder.

Despite this remarkable progress, the current AAV vectors will not be effective in all patients. This is mainly due to issues with immune response, as well as the challenges of delivering the vectors to cells or organs of interest. Some of the most effective treatments tested thus far have been locally injected, such as directly into the eye, where the virus has direct contact with the target cells.

Treatment is more complicated in cases where the vectors must be administered intravenously and travel through the bloodstream. Not only does this increase the chances the virus will be "soaked up" by other non-target cells along the way—thus reducing the strength of the treatment—it also exposes them directly to the immune system.

If the patient has previously been exposed to the natural form of the AAV virus, he or she may have antibodies that will recognize and attack the virus, removing it from the bloodstream before it can reach its target. Even if the patient does not have previous AAV exposure, the first treatment could prime the body to launch an immune response, and prevent the effectiveness of follow-up treatments if they are required.

How exo-AAVs could help

The approach being developed by Maguire and his team stems from a discovery that he and his friend, Johan Skog, PhD, made while both postdoctoral fellows at Mass General. They found that a subset of AAVs that can be exported from the cells used to produce the virus inside of exosomes, which are essentially lipid bubbles. These exosomes can serve as a protective barrier between the virus and the components of the immune system in the bloodstream.

Exo aavs

When inside lipid bubbles (exosomes), AAV may be shielded from neutralization by AAV antibodies. (Image courtesy of the Maguire Lab)

Fast forward 8 years and countless experiments, and Maguire is beginning to see advantages of these exosome-equipped AAV vectors (exo-AAVs), as a delivery device for gene therapy. With collaborators, his group has published several papers showing that exo-AAVs can evade inactivation by antibodies as well as increase delivery to certain target cells.

The team is still working on strategies to refine and improve the technology, and much work needs to be performed before they can be considered by the FDA as a medicine.

But if it works, the strategy could open gene therapy treatments up to a wider range of patients—including those with immunity to AAV.

Collaborations at Mass General and beyond

In the meantime, Maguire is collaborating with disease specialists at Mass General and Harvard Medical School to develop new gene therapy-based treatment strategies for conditions such as muscular dystrophy (with Thurman Wheeler, MD), Alzheimer’s disease (with Rudy Tanzi, PhD, Brad Hyman, PhD, Ana Griciuc, PhD, and Eloise Hudry, PhD), CNS disorders (Florian Eichler, MD, and Xandra Breakefield, PhD) and hereditary deafness (David Corey, PhD, of Harvard Medical School), among others.

"That's probably what I enjoy the most about my job—the people I get to work with," he says."There are so many brilliant scientists at Mass General, and they have identified lots of potential treatment targets. I've found a niche where we can combine a deep understanding of disease biology with my lab's gene therapy technologies. It's really been a fun and exciting team effort so far."

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