14 October 2010. Gene therapy is an important research strategy and carries hope of becoming a viable treatment in neurodegenerative disease. Lentiviruses are widely used to deliver genes to mammalian cells in vivo, but unfortunately, these viral particles infect a wide variety of cell types, requiring careful selection of gene elements to restrict expression to cells of interest. A different approach is described in the October 10 Nature Methods. Researchers led by Christian Buchholz at the Paul Ehrlich Institute, Langen, Germany, modified the outer coat of lentiviruses to display single-chain antibodies that are specific to certain cell surface proteins. As shown below, viral particles studded with antibodies to GluA2/4 AMPA receptor subunits specifically deliver their cargo (in this case, the gene for green fluorescent protein) to glutamatergic neurons in the hippocampus and no other cells.
Lentiviral vectors displaying single-chain antibodies to the GluA2/4 subunits of AMPA receptors specifically transfect glutamatergic neurons with the green fluorescent protein gene (right) when injected into the stratum radiatum (SR) of the mouse brain. Unlike normal lentiviruses (left), the GluA2/4 viruses targeted mostly cells in the dentate gyrus (DG) and CA1 through CA3 fields of the hippocampus. The glia-rich corpus callosum (CC) and lacunosum-moleculare (LM) border showed little transfection. (Reprinted by permission from Macmillan Publishers Ltd: Nature Methods, advance online publication, 10 October 2010 [doi: 10.1038/nmeth.1514])
The targeting method has “unprecedented specificity,” according to the authors, and also works for other cell types, including immune and vascular cells. It could improve gene targeting in experimental settings and may add a level of safety to gene therapies by reducing risks associated with “off-target” gene expression.—Tom Fagan.
Reference:
Anliker B, Abel T, Kneissl S, Hlavaty J, Caputi A, Brynza J, Schneider IC, Munch RC, Petznek H, Kontermann RE, Koehl U, Johnston ICD, Keinanen K, Muller UC, Hohenadl C, Monyer H, Cichutek K, Buchholz CJ. Specific gene transfer to neurons, endothelial cells and hematopoietic progenitors with lentiviral vectors. Nature Methods. 2010 October 10. Abstract
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Specific gene transfer to neurons, endothelial cells and hematopoietic progenitors with lentiviral vectors.
