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Cytokine Gene Therapy in Experimental Allergic Encephalomyelitis by Injection of Plasmid DNA-Cationic Liposome Complex into the Central Nervous System¹

J. Ludovic Croxford^2,*, Kostas Triantaphyllopoulos, Osvaldo L. Podhajcer, Marc Feldmann, David Baker^* and Yuti Chernajovsky

^* Department of Clinical Ophthalmology, Institute of Ophthalmology, University College London, London, United Kingdom; Kennedy Institute of Rheumatology, London, United Kingdom; and Instituto de Investigaciones Bioqúimicas, Fundación Campomar, Facultad Ciencias Exactas y Naturales-Universidad de Buenos Aires, Buenos Aires, Argentina

Experimental allergic encephalomyelitis (EAE) is an autoimmune disease of the central nervous system with many similarities to multiple sclerosis. The main effector cells involved are CD4⁺ T cells, recognizing encephalitogenic epitopes within the central nervous system, and macrophages, both of which secrete proinflammatory cytokines, such as IFN- and TNF. Studies have shown that immunomodulation of this inflammatory response by anti-inflammatory cytokines (IL-4, IL-10, IFN-ß, and TGF-ß) can reduce clinical severity in EAE. The importance of TNF in EAE has been demonstrated by using soluble TNF-receptor molecules to inhibit EAE. However, the limitation of this type of therapy is the necessity for frequent administration of cytokine proteins due to their short biologic half-life. This study demonstrates that EAE can be inhibited by a single injection of therapeutic cytokine (IL-4, IFN-ß, and TGF-ß) DNA-cationic liposome complex directly into the central nervous system. DNA coding for a novel, dimeric form of human p75 TNF receptor also ameliorated clinical EAE. Local administration of DNA-cationic liposome complex has identified gene targets that may be more efficiently exploited using vectors producing more stable expression for effective treatment of neuroimmunologic disease.

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