IL4 gene delivery to the CNS recruits regulatory T cells and induces clinical recovery in mouse models of multiple sclerosis

• Published in: Gene therapy Vol. 15; no. 7; pp. 504 - 515
• Main Authors: Butti, E, Bergami, A, Recchia, A, Brambilla, E, Del Carro, U, Amadio, S, Cattalini, A, Esposito, M, Stornaiuolo, A, Comi, G, Pluchino, S, Mavilio, F, Martino, G, Furlan, R
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-04-2008; Nature Publishing Group
• Subjects: Adenoviridae - genetics; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Animal models; Animals; Applied cell therapy and gene therapy; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Biotechnology; CCL17 protein; CCL22 protein; CD25 antigen; CD4 antigen; CD69 antigen; Cell Biology; Central nervous system; Central Nervous System - immunology; Central Nervous System - pathology; Cerebrospinal fluid; Chemokines; Chemokines - immunology; Chemotaxis, Leukocyte; Cytokines; Disease Models, Animal; Experimental allergic encephalomyelitis; Female; Foxp3 protein; Fundamental and applied biological sciences. Psychology; Gene Expression; Gene Therapy; Gene transfer; Genetic Therapy - methods; Genetic Vectors - administration & dosage; Green Fluorescent Proteins - analysis; Green Fluorescent Proteins - genetics; Health. Pharmaceutical industry; Helper Viruses - genetics; Herpes simplex; Herpes simplex virus; Human Genetics; Humans; Immunology; Immunoregulation; Industrial applications and implications. Economical aspects; Inflammatory diseases; Interleukin 4; Interleukin-4 - analysis; Interleukin-4 - genetics; Interleukin-4 - immunology; Lymphocytes T; Medical sciences; Mice; Mice, Inbred C57BL; Multiple sclerosis; Multiple Sclerosis - immunology; Multiple Sclerosis - pathology; Multiple Sclerosis - therapy; Nanotechnology; Neurology; original-article; Primates; Reverse Transcriptase Polymerase Chain Reaction; Rodents; T-Lymphocytes, Regulatory - immunology; Toxicity; Transduction, Genetic - methods; Transfusions. Complications. Transfusion reactions. Cell and gene therapy; IL4; Treg cells; HD-Ad; foxp3; chemokines; EAE/MS; Foxp3 transcription factor; Animal model; Nervous system diseases; Multiple sclerosis; Hyperactivity; Rodentia; Inflammatory disease; Chemokine; Vertebrata; Mammalia; Attentional disorder; Mouse; Central nervous system disease; Regulatory T cell; Attention disorder with hyperactivity; Gene therapy
• ISSN: 0969-7128; 1476-5462
• DOI: 10.1038/gt.2008.10

Central nervous system (CNS) delivery of anti-inflammatory cytokines, such as interleukin 4 (IL4), holds promise as treatment for multiple sclerosis (MS). We have previously shown that short-term herpes simplex virus type 1-mediated IL4 gene therapy is able to inhibit experimental autoimmune encephalomyelitis (EAE), an animal model of MS, in mice and non-human primates. Here, we show that a single administration of an IL4-expressing helper-dependent adenoviral vector (HD-Ad) into the cerebrospinal fluid (CSF) circulation of immunocompetent mice allows persistent transduction of neuroepithelial cells and long-term (up to 5 months) CNS transgene expression without toxicity. Mice affected by chronic and relapsing EAE display clinical and neurophysiological recovery from the disease once injected with the IL4-expressing HD-Ad vector. The therapeutic effect is due to the ability of IL4 to increase, in inflamed CNS areas, chemokines (CCL1, CCL17 and CCL22) capable of recruiting regulatory T cells (CD4
+
CD69
−
CD25
+
Foxp3
+
) with suppressant functions. CSF delivery of HD-Ad vectors expressing anti-inflammatory molecules might represent a valuable therapeutic option for CNS inflammatory disorders.