Vaccines, Blood & Biologics

FDA scientists discover how to shield gene therapy vectors against attack by the immune system


Scientists at the US Food and Drug Administration (FDA) have discovered how certain virus vectors being used in gene therapy ward off attack from the immune system, a finding that will help researchers to design effective gene therapy vectors. The FDA scientists made their discovery while studying a common cold virus called adenovirus that is widely used as a gene therapy vector—a means to deliver genes into human cells. The FDA scientists discovered that adenovirus commandeers a protein called clotting factor X (FX) from the blood and uses it as a shield to evade attack by the immune system.
The FDA finding is important because the immune system can recognize and attack viruses, and is a roadblock to delivering gene therapy vectors through the bloodstream. The discovery that adenovirus disguises itself from the immune system using one of the body’s own proteins gives researchers a new strategy to design efficient gene therapy vectors that will survive in the bloodstream.
FX is one of about a dozen clotting factor proteins that interact in a series of chemical reactions to make blood clots. Previous studies from other laboratories had showed that adenovirus scavenges FX protein from the bloodstream and puts this protein on its surface. However, until now it has been unclear why adenovirus does this. The common wisdom among scientists has been that adenovirus uses FX as a bridge to link itself to liver cells. Many researchers have been searching for ways to prevent adenovirus from binding to liver cells so that researchers can direct adenovirus to other target tissues, such as tumors. Because FX has been thought to be essential for adenovirus to bind to liver cells, one proposed strategy to prevent adenovirus from binding to liver cells was to remove FX from adenovirus.  
The FDA scientists showed that adenovirus does not actually need FX for binding to liver cells. Instead, adenovirus uses FX to disguise itself from the immune system’s so-called “complement system” – a series of proteins that rapidly attacks foreign substances and infectious microorganisms in the bloodstream. The FDA scientists demonstrated that removing FX leaves adenovirus defenseless against complement proteins that inactivate the virus. This suggests that when researchers design vectors that are intended for delivery through the bloodstream, researchers also need to engineer mechanisms to protect these vectors from attack by complement proteins.  
This discovery represents a major change in thinking about the design of gene therapy vectors. Researchers now must take into consideration how to protect vectors from complement proteins, in order to ensure that these vectors survive contact with immune defenses in the blood. The discovery of the novel “disguise” defense used by adenovirus will enhance researcher’s ability to use viruses as gene therapy vectors.

Nature Medicine


Zhili Xu,1 Qi Qiu,1 Jie Tian,1 Jeffrey S Smith,1 Gina M Conenello,1 Takashi Morita2 & Andrew P Byrnes1
1Office of Cellular, Tissue and Gene Therapy, Center for Biologics Evaluation and Research, US Food and Drug Administration, Bethesda, Maryland.
2Mejii Pharmaceutical University, Tokyo, Japan

Page Last Updated: 08/17/2015
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