A single intrathecal injection of DNA and an asymmetric cationic lipid as lipoplexes ameliorates experimental autoimmune encephalomyelitis

Srikanth Yellayi, Brendan Hilliard, Mustafa Ghazanfar, Akivaga Tsingalia, Michael H. Nantz, Laura Bollinger, Fabian De Kok-Mercado, James G. Hecker

Research output: Contribution to journalArticle

5 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1980-1984
Number of pages5
JournalMolecular Pharmaceutics
Volume8
Issue number5
DOIs
StatePublished - Oct 3 2011
Externally publishedYes

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Keywords

  • animal model
  • asymmetric lipids
  • CNS gene delivery
  • experimental autoimmune encephalomyelitis

ASJC Scopus subject areas

  • Pharmaceutical Science
  • Molecular Medicine
  • Drug Discovery

Cite this

Yellayi, S., Hilliard, B., Ghazanfar, M., Tsingalia, A., Nantz, M. H., Bollinger, L., De Kok-Mercado, F., & Hecker, J. G. (2011). A single intrathecal injection of DNA and an asymmetric cationic lipid as lipoplexes ameliorates experimental autoimmune encephalomyelitis. Molecular Pharmaceutics, 8(5), 1980-1984. https://doi.org/10.1021/mp2002413