Children's Hospital Researchers Develop Bioengineered Decoy to Improve Gene Therapy

Gene therapy researchers at The Children’s Hospital of Philadelphia have produced a bioengineered decoy that by fooling the immune system prevents it from undermining the benefits delivered by a corrective gene. The decoy could offer a new treatment for genetic diseases while advancing the broader field of gene therapy if the approach succeeds in humans.

“This decoy strategy could be individualized to patients and could greatly expand the population of patients who may benefit from gene therapy,” said the study’s leader, Katherine A. High, MD, director of Children’s Hospital’s Center for Cellular and Molecular Therapeutics (CCMT). “Right now, 30 to 60 percent of adult patients develop antibodies that block the ability of an intravenously infused vector to reach the target cells in the liver. This approach holds the promise of overcoming this roadblock — pre-existing antibodies — and allowing successful intravenous gene therapy in virtually all adult patients.”

In earlier clinical trials, Dr. High and her team used adeno-associated virus (AAV) as a vector (or delivery vehicle) to ferry a corrective DNA sequence to patients with a mutation causing hemophilia B, the second most common form of the disease. However, there’s a catch: though AAV does not cause human disease, because we are routinely exposed to the virus 30 to 60 percent of people develop antibodies that neutralize AAV if it enters the circulation. Researchers have long sought ways to better manage this immune response, and Dr. High’s decoy strategy could help solve this challenge.

In the current study, published recently in Science Translational Medicine, Dr. High and her team investigated capsids, the protein shells that surround viruses. The researchers injected empty AAV capsids along with gene therapy vectors into a mouse model, and found that the anti-AAV neutralizing antibodies bound to the capsid decoys, allowing the DNA-carrying vectors to evade the antibodies and enter the targeted cells in the liver.

The study team next engineered the capsids to disable their ability to enter target cells. This prevented the capsids from triggering a second immune response, from T cells, that also could eliminate the corrective genes. The gene therapy was found to be safe and effective in monkeys.

“Our results, which held up over a range of doses, suggest that in clinical studies, it will be feasible to adjust the ratio of empty capsids to gene vector doses, depending on an individual’s pre-existing level of neutralizing antibodies,” said Dr. High. “That means we could personalize gene therapy to make it more efficient for each patient.”

For more information about the work being done at the Center for Cellular and Molecular Therapeutics, see the Center’s website.