Gene Therapy Advanced by Structural Study of Potential Viral Vectors

    Scientists led by associate professor Vijay Reddy, Ph.D., at The Scripps Research Institute (TSRI) say they have discovered the structural details that make one virus a better tool for future therapies than a closely related virus. The team wrote in Science Advances (“Cryo-EM Structure of Human Adenovirus D26 Reveals the Conservation of Structural Organization among Human Adenoviruses”) that the structure of a less prevalent species D adenovirus may work well as a gene-delivery vector because its structure doesn’t allow it to wind up in the liver, thus minimizing liver toxicity. The Reddy lab’s study reportedly is the first to show the structural details on species D’s surface that set it apart from another common subtype of adenovirus, called species C, which does travel to the liver.

    “Greater understanding of the structures of adenoviruses from different species will help generate better gene therapies and/or vaccine vectors,” said Dr. Reddy.

    Using cryo-electron microscopy, the researchers discovered that while these two species of adenoviruses share the same shell-like core, they have different surface structures, called decorations or loops, which are key to a virus’s behavior. They determine which receptors on human cells the virus can bind to. For species C adenoviruses, specific loops help the virus attach to blood coagulation factors (adaptor proteins) and get targeted to the human liver. Species D adenoviruses display distinctly different loop decorations. For use in gene and vaccine therapies, the virus would deliver helpful genes instead.

    Species D also has one more important advantage over species C: Humans are constantly exposed to species C adenoviruses, so most people have developed antibodies to fight them off. These same antibodies would fight off the species C viruses even if they were designed for beneficial therapies. On the flip side, many of the species D adenoviruses are rare, and it’s unlikely that a patient would have antibodies to fight them off, according to the investigators. That makes species D viruses better for delivering therapies, explains Dr. Reddy, who adds that scientists are already testing ways to use it to generate malaria and Ebola virus vaccines.

    The researchers next plan to look at members of the other five adenovirus species to see if they would have useful traits as viral therapy vectors.