One dose of "designer" gene therapy may target specific body area

“It may be possible to design and construct genetically engineered ‘designer’ gene therapy for selectively delivering genes to any part of the body,” said Andrew H. Baker, Ph.D., lead investigator of the study and a reader in molecular medicine at the University of Glasgow in Scotland. “We can’t do that now because much of what’s injected would be sequestered by the liver.” The liver cleanses the blood of foreign material, among other functions.

Gene therapy involves inserting the treatment genes into a virus that is either harmless to humans or has had its disease-causing component removed. The virus is then injected or inserted into the body where it “infects” an area with gene therapy.

Baker’s team redesigned a virus called adeno-associated virus (AAV) so that it is not quarantined by the liver, but rather remained in the bloodstream long enough to “infect” specific cells in the body — in this case, the vascular endothelial cells (ECs).

The new therapy targets vascular endothelial cells, which line the inside of blood vessels.

“Vascular endothelial cells, which are in continuous contact with the bloodstream and integrally involved in cardiovascular abnormalities, are appropriate targets for gene therapy,” Baker said.

Baker said that AAV is important because it has the potential for long-term gene expression from a single dose. This is based on results from hemophilia studies from other laboratories in which the virus was used to deliver gene therapy. In these studies, Baker said that a single dose could last up to five years, possibly longer as the studies are ongoing. AAV is also a good choice because it does not cause disease in humans.

“The concept of developing systematically injectable gene transfer vehicles is important for a number of potential cardiovascular gene therapies, particularly in those conditions where access to the target site can only realistically be achieved via the bloodstream” he said. “This work shows for the first time that this is possible using cell-specific peptides to modify AAV vehicles for systemic gene delivery.

Researchers modified the virus with two new peptides, or small proteins, that bind specifically to ECs. They inserted these peptides into the virus to create endothelial cell-selective proteins to make, essentially, a designer virus, Baker said.

The peptides are called msl and mtp. The unmodified form of AAV is called the “wild type,” or AAVwt. The modified forms of the virus are called AAVmsl and AAVmtp.

Baker and his colleagues studied how the modified viruses interacted with endothelial cells in the laboratory as well as in mice.

In laboratory studies, researchers showed that the unmodified virus was 100 times more infective in liver cells than in ECs. The modified virus, however, had more favorable infectivity for vascular ECs, Baker said.

In mouse studies, the modified viruses accumulated at lower levels than the wild type in the major organs, predominantly the liver. Secondly, the modified AAV remained in the blood circulation longer than wild-type AAV, presumably because of reduced liver sequestration. Also, the modified virus accumulated at the target vascular endothelial site.

Baker said that his results could improve the selectivity and efficiency of gene delivery to the cardiovascular system, which could also improve the safety of using it.

Co-authors are Steve D. White, D. Phil.; Stuart A. Nicklin, Ph.D.; Hildegard Büning, Ph.D.; M. Julia Brosnan, Ph.D.; Kristen Leike; Emmanuel D. Papadakis, B.Sc.; and Michael Hallek, M.D.

NR04 – 1186 (Circ/White-Baker)

©2004 American Heart Association, Inc.

Stephen J. White, Stuart A. Nicklin, Hildegard Büning, M. Julia Brosnan, Kristen Leike, Emmanuel D. Papadakis, Michael Hallek, and Andrew H. Baker
Targeted Gene Delivery to Vascular Tissue In Vivo by Tropism-Modified Adeno-Associated Virus Vectors
Circulation, Jan 2004

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