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Immunological thresholds in neurological gene therapy: highly efficient elimination of transduced cells might be related to the specific formation of immunological synapses between T cells and virus-infected brain cells

机译:神经基因治疗中的免疫学阈值:高效消除转导细胞可能与T细胞和病毒感染的脑细胞之间免疫突触的特定形成有关

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摘要

First-generation adenovirus can be engineered with powerful promoters to drive expression of therapeutic transgenes. Numerous clinical trials for glioblastoma multiforme using first generation adenoviral vectors have either been performed or are ongoing, including an ongoing, Phase III, multicenter trial in Europe and Israel (Ark Therapeutics, Inc.). Although in the absence of anti-adenovirus immune responses expression in the brain lasts 6–18 months, systemic infection with adenovirus induces immune responses that inhibit dramatically therapeutic transgene expression from first generation adenoviral vectors, thus, potentially compromising therapeutic efficacy. Here, we show evidence of an immunization threshold for the dose that generates an immune response strong enough to eliminate transgene expression from the CNS. For the systemic immunization to eliminate transgene expression from the brain, ≥1 × 107 infectious units (iu) of adenovirus need to be used as immunogen. Furthermore, this immune response eliminates >90% of transgene expression from 1 × 107–1 × 10³ iu of vector injected into the striatum 60 days earlier. Importantly, elimination of transgene expression is independent of the nature of the promoter that drives transgene expression and is accompanied by brain infiltration of CD8+ T cells and macrophages. In conclusion, once the threshold for systemic immunization (i.e. 1 × 107 iu) is crossed, the immune response eliminates transgene expression by >90% even from brains that receive as little as 1000 iu of adenoviral vectors, independently of the type of promoter that drives expression.
机译:可以用强大的启动子工程化第一代腺病毒,以驱动治疗性转基因的表达。使用第一代腺病毒载体进行的多形胶质母细胞瘤的许多临床试验已经进行或正在进行中,包括正在进行的在欧洲和以色列进行的III期多中心试验(Ark Therapeutics,Inc.)。尽管在大脑中没有抗腺病毒免疫反应的表达持续6到18个月,但是腺病毒的全身感染会诱导免疫反应,从而大大抑制第一代腺病毒载体治疗性转基因的表达,从而潜在地损害治疗效果。在这里,我们显示了足以产生足以消除中枢神经系统转基因表达的免疫反应的剂量的免疫阈值的证据。为了从脑中进行全身免疫以消除转基因表达,需要使用≥1×10 7 腺病毒感染单位(iu)作为免疫原。此外,这种免疫反应可消除60天前注射到纹状体中的1×10 7 –1×10³iu载体中> 90%的转基因表达。重要的是,消除转基因表达与驱动转基因表达的启动子的性质无关,并伴有CD8 + T细胞和巨噬细胞的脑浸润。总之,一旦超过了全身免疫的阈值(即1×10 7 iu),即使从仅接受1000 iu腺病毒载体的大脑中,免疫反应也会消除转基因表达> 90%。 ,与驱动表达的启动子类型无关。

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