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Scientists Report Advances in Novel Gene Therapy Vector

A team of researchers at the University of Florida (UF) in Gainesville has reported a potential gene therapy breakthrough using an altered viral vector (a nondisease-causing vehicle that transfers genetic material) that is significantly more efficient than current vectors. The report suggests that by substituting a particular amino acid found on the surface of the virus, superior therapeutic benefits can be achieved for hemophilia and other genetic diseases. The lead author of the study is Arun Srivastava PhD, the George H. Kitzman professor of genetics and the chief of cellular and molecular therapy in the UF College of Medicine.

While adeno-associated viruses (AAV) are considered by many scientists as optimal gene therapy vectors--they can be used to infect cells without causing disease--they have several drawbacks. Often, trillions of AAV particles need to be administered for the corrective gene to eventually “take root” in the nucleus of a cell and carry out its therapeutic function. Past studies have shown that AAV and some other vectors delivered in such a high volume trigger an immune response in the host.

“Based on our studies and those of others, it’s become clear that the reason you need so much is because about half the AAV particles get stuck in the cytoplasm. It doesn’t get to the nucleus very efficiently,” said Srivastava. “AAV is seen by the body as an invading protein and it tries to block it.” In these cases, the body identifies many of the AAV particles as unwelcome proteins and deposits them in cellular trash receptacles, called proteasomes, to be destroyed. As this process occurs, the chemical compound phosphate binds to the hydroxyl group of molecules, indicating to the proteasome that it can carry out its disposal function.

The amino acid tyrosine, on the surface of a virus, contains the hydroxyl group molecules and therefore becomes a key target. By removing it and replacing it with phenylalanine, another amino acid, Srivastava and his team were able to circumvent the response. Tyrosine and phenylalanine are identical in all but one important way--phenylalanine lacks the structure that attracts phosphate.

Since tyrosine is found at seven spots on the surface of AAV, the scientists created seven new vectors, exchanging a different tyrosine in each one, and inserting in each the gene that elicits the production of clotting factor IX (fIX). (Hemophilia B patients produce insufficient amounts of fIX.)

When tested in tissue samples and mice, all of the altered vectors showed superior results, as compared to a typical version of AAV. One version worked 11 times better in tissue samples after 48 hours. Another new AAV vector was working 29 times better than the standard vector at integrating the new gene into cells two weeks after the mice were injected with the therapeutic gene. Notably, this was achieved at a 10-fold lower dose.

“We were very surprised. It’s amazing to think that changing one amino acid could produce these results,” said Srivastava. “Now the virus actually completely avoids being phosphorylated, so it doesn’t become degraded and it goes into the nucleus, and we get therapeutic levels of proteins. We can generate therapeutic levels of factor IX.”

Srivastava also said that this novel type of AAV could not only be more efficient but less expensive as well. A traditional AAV therapy can require more than 10 trillion AAV particles, whereas the new AAV therapy could use as few as 100 billion particles.

The next step will be to test the therapy in other animals. Srivastava’s team will collaborate with researchers at the University of North Carolina to test the new AAV vectors in dogs with hemophilia. If these studies are successful, they could pave the way for human gene therapy trials.

The study, “Next generation of adeno-associated virus 2 vectors: Point mutations in tyrosines lead to high-efficiency transduction at lower doses,” was published in the early edition of the May 29, 2008, online version of the Proceedings of the National Academy of Sciences.

Source: University of Florida news release dated May 19, 2008


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