Intravenous, non-viral RNAi gene therapy of brain cancer.
RNA interference (RNAi) has the potential to knock down oncogenes in cancer, including brain cancer. However, the therapeutic potential of RNAi will not be realised until the rate-limiting step of delivery is solved. The development of RNA-based therapeutics is not practical, due to the instability of RNA in vivo. However, plasmid DNA can be engineered to express short hairpin RNA (shRNA), similar to endogenous microRNAs. Intravenous, non-viral RNAi-based gene therapy is enabled with a new gene-targeting technology, which encapsulates the plasmid DNA inside receptor-specific pegylated immunoliposomes (PILs). The feasibility of this RNAi approach was evaluated by showing it was possible to achieve a 90% knockdown of brain tumour-specific gene expression with a single intravenous injection in adult rats or mice with intracranial brain cancer. The survival of mice with intracranial human brain cancer was extended by nearly 90% with weekly intravenous injections of PILs carrying plasmid DNA expressing a shRNA directed against the human epidermal growth factor receptor. RNAi-based gene therapy can be coupled with gene therapy that replaces mutated tumour suppressor genes to build a polygenic approach to the gene therapy of cancer.
Department of Medicine, UCLA, Warren Hall 13-164, 900 Veteran Ave, Los Angeles, CA 90024, USA. wpardridge@mednet.ucla.edu
William M
WM
Pardridge
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000493:pharmacokinetics; D001812:Blood-Brain Barrier; D001932:Brain Neoplasms / Q000628:therapy*; D004337:Drug Carriers; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics; D005240:Feasibility Studies; D015972:Gene Expression Regulation, Neoplastic; D018390:Gene Targeting; D017930:Genes, Reporter; D005910:Glioma / Q000628:therapy; D006801:Humans; D007275:Injections, Intravenous; D008081:Liposomes; D008156:Luciferases / Q000235:genetics; D008253:Macaca mulatta; D051379:Mice; D016513:Mice, SCID; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D009857:Oncogenes; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000493:pharmacokinetics; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000627:therapeutic use*; D051381:Rats; D011972:Receptor, Insulin / Q000037:antagonists & inhibitors / Q000235:genetics; D011990:Receptors, Transferrin / Q000037:antagonists & inhibitors / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D004337:Drug Carriers; D008081:Liposomes; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; D011990:Receptors, Transferrin; D011092:Polyethylene Glycols; D008156:Luciferases; D066246:ErbB Receptors; D011972:Receptor, Insulin