AAV shows promise as mutation repair vector

Adeno-associated virus (AAV) shows promise as a gene-targeting vector for repair of mutations, particularly in cell populations that can be treated ex vivo and reinfused back into the host, according to David Russell, a professor at the University of Washington.

Russell described ex vivo experiments using an AAV targeting vector to homologously inactivate a dominant-negative mutation in the human type 1 collagen gene COL1A1 gene, which causes the brittle bone disease osteogenesis imperfecta.

Using a vector, which inserted a selectable sequence disrupting the gene upstream of the mutation, the researchers demonstrated that more than 90 per cent of mesenchymal stem cells from patients with OI had undergone gene targeting after a single round of selection. The modified cells were able to undergo in vitro differentiation to bone and fat cells, indicating that the multipotency of the stem cells was not affected. Good results were also achieved without selection, in polyclonal populations of cells.

Russell said that the method would be suitable for a number of different cell types, including other types of stem cells, as a correction therapy for diseases involving dominant-negative mutations, where knocking out the mutated form of the gene corrected the phenotype.

"Stem cells are the most practical at this point -- they can be done ex vivo," he said.

But the therapy is still a long way from the clinic, and Russell said that the arduous regulatory process required for gene therapy trials was also a factor.