title: A single intrathecal injection of DNA and an asymmetric cationic lipid as lipoplexes ameliorates experimental autoimmune encephalomyelitis.
abstract: Intrathecal delivery of gene therapeutics is a route of administration that overcomes several of the limitations that plague current immunosuppressive treatments for autoimmune diseases of the central nervous system (CNS). Here we report intrathecal delivery of small amounts (3 μg) of plasmid DNA that codes for an immunomodulatory fusion protein, OX40-TRAIL, composed of OX40, a tumor necrosis factor receptor, and tumor necrosis factor related apoptosis inducing ligand (TRAIL). This DNA was delivered in a formulated nucleic acid-lipid complex (lipoplexes) with an asymmetric two-chain cationic lipid myristoyl (14:0) and lauroyl (12:1) rosenthal inhibitor-substituted compound (MLRI) formed from the tetraalkylammonium glycerol-based compound N-(1-(2,3-dioleoyloxy)-propyl-N-1-(2-hydroxy)ethyl)-N,N-dimethyl ammonium iodide. Delivery and expression in the CNS of OX40-TRAIL in the mouse prior to onset of experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis, decreased the severity of clinical disease. We believe this preclinical demonstration of rapid, widespread, and biologically therapeutic nonviral gene delivery to the CNS is important in further development of clinical lipid-based therapeutics for CNS disorders.
authors: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6112, United States.
authors: Srikanth
authors: S
authors: Yellayi
authors: Brendan
authors: B
authors: Hilliard
authors: Mustafa
authors: M
authors: Ghazanfar
authors: Akivaga
authors: A
authors: Tsingalia
authors: Michael H
authors: MH
authors: Nantz
authors: Laura
authors: L
authors: Bollinger
authors: Fabian
authors: F
authors: de Kok-Mercado
authors: James G
authors: JG
authors: Hecker
mesh_terms: D000818:Animals; D002490:Central Nervous System / Q000378:metabolism; D002946:Cisterna Magna; D004247:DNA / Q000008:administration & dosage / Q000737:chemistry*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D005260:Female; D015870:Gene Expression; D018014:Gene Transfer Techniques; D017930:Genes, Reporter; D015316:Genetic Therapy; D007278:Injections, Spinal; D007848:Laurates / Q000737:chemistry; D008055:Lipids / Q000008:administration & dosage / Q000737:chemistry*; D051379:Mice; D008810:Mice, Inbred C57BL; D009103:Multiple Sclerosis / Q000378:metabolism / Q000628:therapy; D009226:Myristates / Q000737:chemistry; D010957:Plasmids / Q000008:administration & dosage / Q000737:chemistry; D053262:Receptors, OX40 / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013228:Stearates / Q000008:administration & dosage / Q000737:chemistry; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism
chemical_list: D007848:Laurates; D008055:Lipids; D009226:Myristates; D053262:Receptors, OX40; D011993:Recombinant Fusion Proteins; D013228:Stearates; D053221:TNF-Related Apoptosis-Inducing Ligand; C015161:Rosenthal's inhibitor; D004247:DNA