LA JOLLA, Calif.—With all the excitement around CRISPR/Cas 9 you might have briefly forgotten about the good old (well, “old” being relative with the speed of scientific advancement and change these days on the gene therapy front) acronym AAV—the adeno-associated virus way of doing things in gene therapies.
Well, you probably didn’t forget, but AAV might have slipped a bit to a burner slightly farther back on the metaphorical stovetop of gene therapy R&D.
In any case, recent work at The Scripps Research Institute (TSRI) has researchers saying that they have now uncovered the structural details that make one particular virus a better tool for future therapies than its closely related cousin. As TSRI notes, “In their quest to replicate themselves, viruses have gotten awfully good at tricking human cells into pumping out viral proteins. That’s why scientists have been working to use viruses as forces for good: to deliver useful genes to human cells and help patients who lack important proteins or enzymes.”
And what is this TSRI team—led by associate professor Vijay Reddy—talking about specifically? Well, as they reported in May in the article “Cryo-EM structure of human adenovirus D26 reveals the conservation of structural organization among human adenoviruses” in the journal Science Advances, there is a species D adenovirus—HAdV-D26 is what they focused on in the study—that is a less prevalent adenovirus but which may have great utility as a gene-delivery vector. The reason is because its structure keeps it from being whisked away to the liver, and this means potentially much less risk of liver toxicity from AAV gene therapy if this version of the adenovirus does what they hope it will in humans.
“Greater understanding of the structures of adenoviruses from different species will help generate better gene therapies and/or vaccine vectors,” said Reddy—his lab’s study is reportedly 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. The team discovered that while the two species of adenoviruses have the same kind of shell-like core, cryo-electron microscopy was able to reveal that they have different surface structures, which Reddy called “decorations” or “loops.”
As noted by TSRI, these loops are key to a virus’ behavior, determining 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, while species D does not.
As noted in the 2011 article “Molecular evolution of human species D adenoviruses” in the journal Infection, Genetics and Evolution, “The first HAdV-D type to be classified was HAdV-D8, a major etiologic agent of epidemic keratoconjunctivitis ... HAdV-D types have been isolated from the upper and lower respiratory, gastrointestinal, and genitourinary tracts, and the eye.” In the case of HAdV-D26, which the Reddy Lab used, the virus is associated with infection of the eye.
According to TSRI, species D has another advantage over species C in terms of delivering gene therapies, in that humans are constantly exposed to species C adenoviruses. As such, most people have developed antibodies to fight them off, which would be a potential barrier even if the virus were carrying beneficial therapies. However, many of the species D adenoviruses are rare, making it less likely that a patient would have antibodies to hinder them and making them a theoretically better set of adenoviruses for delivering therapies.
According to Reddy, scientists are already testing ways to use species D viruses to generate malaria and Ebola virus vaccines.
The TSRI researchers, for their part, say their next steps are to look at members of the other five species of adenoviruses to see if they would have useful traits as viral therapy vectors.
