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Today's Viral Vectors
The most promising viral vectors produced after nearly a decade of research are adenovirus (AV) and adeno-associated virus (AAV). Adenovirus (one of the causes of the common cold) has been engineered to remove the genes
that cause it to replicate, while adeno-associated virus, as its name implies, depends on AV to reproduce and so needs no special tinkering to ensure its safety, and causes no known disease. In some ways, the two vectors are complementary: AV packs a punch, delivering a big genetic payload quickly, but it is a complex virus and thus is rapidly detected and eliminated by the immune system. It also can cause a toxic immune response at too high of a dose. AAV is a "low, slow" delivery vector, achieving lower efficiency of gene transfer but, because it can delivery its genes across the nuclear membrane, it incorporates the genes it carries into the cellular genome and induces longer-term gene expression. A limiting factor of AAV is the size of the gene it can carry--about 5 kilobases, big enough for most genes, but not all.
At the December meeting of the American Society of Hematology, researchers at Avigen, Inc. (Alameda, CA) reported using AAV to express factor IX (deficient in some hemophiliacs) in five dogs for over a year, while researchers at Cell Genesys, Inc. (Foster City, CA) in the January issue of Nature Medicine, reported using AAV to express factor IX in dogs for up to seventeen months.
Retroviruses have also made a comeback, in the form of the HIV-related lentiviruses. These vectors haven't reached the clinic, but early reports suggest they can infect across the nuclear membrane to produce long-term gene expression, and they may be able to evade detection by the immune system. They have their disadvantages, of course. Lentivirus vectors will almost certainly confront big regulatory hurdles because FDA would look askance upon any therapeutic delivery system derived from the same virus that causes AIDS. "But the bottom line is whether it works," says Dr. James Wilson, director of the Institute for Human Gene Therapy at the University of Pennsylvania, and a founder and consultant for Philadelphia-based Genovo Inc. "If it really works, then that would justify its application, at least in the early days" of gene therapy vectors.
And researchers are antsy to find vectors that work. "How do you get enough of the vector to the cell? How do you get them to diffuse through capillaries to the target cells? Right now, we usually have to inject directly into the organ, and that's not very efficient. I think the delivery issues are going to be the most compelling" factor in future gene therapy research, says Wilson.
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