Both retro- and adenovirus-mediated gene therapy have been suggested as a novel approach to the treatment of malignant brain tumors. However, little information is available about the gene transfer efficiency in human malignant glioma in vivo. We compared the feasibility and safety of retrovirus- and adenovirus-mediated beta-galactosidase gene transfer in human malignant glioma. Beta-galactosidase gene was transferred to 10 patients with malignant glioma via a catheter inserted into the tumor. The catheter was left in place until the tumor resection. To maximize gene transfer efficiency, gene transfer vectors (BAG retroviruses, titer, 6 x 10(5) CFU; and adenoviruses, titer from 3 x 10(8) to 3 x 10(10) PFU) were injected into the tumor via the catheter once a day for three consecutive days, followed by tumor resection 1-2 days later. Tumor was resected in such a way that the catheter was still in place inside the tumor, which permitted accurate histological analysis of the transduced tumors. X-Gal staining for beta-galactosidase activity was used to study gene transfer efficiency and distribution of the marker gene. Beta-galactosidase gene transfer was well tolerated with both vectors. Except for two patients with clear increases in serum adenovirus antibody titers, no adverse tissue responses or systemic complications were noticed in any of the patients. Gene transfer was successful in all patients. Gene transfer efficiency varied between <0.01 and 4% with retroviruses and between <0.01 and 11% with adenoviruses. However, the transgene activity was not evenly distributed in the tumors. Both glioma cells and endothelium in the tumor blood vessels were transduced with retro- and adenovirus vectors. In conclusion, the safety and feasibility of in vivo gene transfer to human malignant glioma was established with retro- and adenovirus vectors. Adenoviruses were more efficient than retroviruses in achieving in vivo gene transfer. Transduction of endothelial cells may have important consequences for the proposed treatment strategies and selection of treatment genes. The results justify clinical gene therapy trials for malignant glioma.
Adenovirus-mediated VEGF-C gene transfer may be useful for the treatment of postangioplasty restenosis and vessel wall thickening after vascular manipulations.
Background-Macrophage scavenger receptors (MSRs) play an important role in the pathogenesis of atherosclerosis.Therefore, local modulation of MSR activity could have a beneficial effect on atherogenesis. Methods and Results-We cloned a secreted "decoy" MSR (sMSR) that contains an extracellular portion of the human MSR type AI and constructed an adenoviral vector that directs high-level expression of sMSR in macrophages under the control of the human CD68 promoter. Expression of the sMSR protein inhibited the degradation of 125 I-labeled acetylated LDL and oxidized LDL by murine macrophages up to 90%. sMSRs also reduced acetylated LDL degradation in MSR knockout mouse peritoneal macrophages by 60% to 80%, which suggests that the decoy construct can compete for the uptake mediated via other related scavenger receptors. In addition, sMSRs inhibited foam-cell formation in murine macrophages in the presence of cytochalasin D. The mechanism of inhibition is through ligand binding to the sMSRs, which prevents the ligand binding to MSRs on cell membranes. Conclusions-The demonstration that recombinant adenovirus-mediated gene transfer of decoy sMSRs can block foam-cell formation suggests a possible new strategy for gene therapy of atherosclerosis and for the treatment of lipid accumulation after arterial manipulations.
We have constructed a novel fusion protein "Scavidin" consisting of the macrophage scavenger receptor class A and avidin. The Scavidin fusion protein is transported to plasma membranes where the avidin portion of the fusion protein binds biotin with high affinity and forms the basis for the targeted delivery of biotinylated molecules. Subcellular fractionation analysis, immunostaining, and electron microscopy demonstrated endosomal localization of the fusion protein. According to pulse-labeling and cross-linking studies Scavidin is found as monomers (55 kDa), dimers, and multimers, of which the 220-kDa form was the most abundant. The biotin binding capacity and active endocytosis of the biotinylated ligands were demonstrated in rat malignant glioma. Local Scavidin gene transfer to target tissues could have general utility as a universal tool to deliver biotinylated molecules at systemic low concentrations for therapeutic and imaging purposes, whereby high local concentration is achieved.
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