‘PILs’ that Cross the Blood Brain Barrier
Authors: Robert M. Frederickson
Journal: Molecular Therapy (2003)

Pegylated immunoliposomes (PILs) are non-viral gene vectors comprising plasmid DNA encapsulated in liposomes bound to polyethylene glycol that is in turn tethered to receptor-targeting antibodies. On page 11 of this issue, William Pardridge and colleagues use these agents to direct strong transient gene expression in the non-human primate brain by intravenous injection. To target the primate brain, they used a monoclonal antibody against the human insulin receptor. They show widespread neuronal expression of both luciferase and -galactosidase reporter genes in response to a single intravenous injection of these so-called “artificial viruses.” Although viral vectors are quite adept at cell entry and gene delivery, their native tropism must often be ablated or changed to be of use for therapeutic gene delivery. Adenoviral vectors are largely based on the Ad5 subgroup that binds the CAR receptor. On page 26, Martin Friedlander and colleagues report the retargeting of Ad5-based vectors to cell types of interest in the treatment of blindness, such as the retinal photoreceptor. Ad3- and Ad37 pseudotyped viruses transduced the ciliary body and photoreceptors, suggesting that these altered vectors might be of use to treat diseases such as glaucoma or degenerative retinal diseases. Gene transfer to the airway epithelia has been proposed as a therapy to treat cystic fibrosis. While adenoviral transfer of genes to the luminal surface is relatively inefficient, transfer to the basolateral side of airway cells is much more effective, due to an asymmetric distribution of the CAR receptors on these membranes. Modification of cell permeability has enhanced epithelial gene transfer in vitro by permitting adenoviral diffusion to the basolateral side where it can bind its receptor. On page 18, Gregory and colleagues now show that sodium caprate, which can open tight junctions, enhances gene transfer by adenoviruses both in vivo and ex vivo. Hammerhead ribozymes are catalytic RNA molecules derived from a self-cleaving plant viral RNA that possess endoribonuclease activity. They have been exploited to inhibit expression of target genes in vitro and even in vivo, by engineering them to contain sequences homologous to a target gene of choice. To date, target sites have been selected through use of computer programs, although the resulting ribozymes have not proven very active in cells. On page 128, Gary Clawson and colleagues present an improved library-based method of creating ribozymes that target accessible sites with high activity in cultured cells. When most of us think of oncolytic viruses, we think of adenovirus or herpes simplex virus, both of which have now been tested in clinical trials. On page 61, Adele Fielding and colleagues describe their efforts to engineer measles virus to transduce selectively non- Hodgkin lymphoma (NHL) cells. Attenuated measles virus has previously been shown to cause regression of human lymphoma xenografts in SCID mice. In the new report, the workers enhance the ability of the virus to kill tumor cells by engineering into viral envelope proteins a single chain Fv that recognizes a clinically-relevant NHL antigen, CD20.