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
Neuroimmunology Unit, San Raffaele Scientific Institute, Milan, Italy.
Gene Ther. 2008 Apr;15(7):504-15. doi: 10.1038/gt.2008.10. Epub 2008 Jan 31.
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.
向中枢神经系统（CNS）递送抗炎细胞因子，如白细胞介素4（IL4），有望成为治疗多发性硬化症（MS）的方法。我们之前已经表明，短期单纯疱疹病毒1型介导的IL4基因疗法能够在小鼠和非人灵长类动物中抑制实验性自身免疫性脑脊髓炎（EAE），这是一种MS的动物模型。在此，我们表明，向具有免疫活性的小鼠的脑脊液（CSF）循环中单次注射表达IL4的辅助依赖型腺病毒载体（HD-Ad），可使神经上皮细胞持续转导，并实现长期（长达5个月）的CNS转基因表达且无毒性。一旦注射表达IL4的HD-Ad载体，患有慢性复发性EAE的小鼠会从疾病中实现临床和神经生理学恢复。治疗效果归因于IL4能够在炎症的CNS区域增加趋化因子（CCL1、CCL17和CCL22），这些趋化因子能够募集具有抑制功能的调节性T细胞（CD4 + CD69 - CD25 + Foxp3 +）。递送表达抗炎分子的HD-Ad载体至CSF可能是治疗CNS炎症性疾病的一种有价值的治疗选择。
