PDF(Pubmed)
Abstract：
Viral vector gene therapy has immense promise for treating central nervous system (CNS) disorders. Although adeno-associated virus vectors (AAVs) have had success, their small packaging capacity limits their utility to treat the root cause of many CNS disorders. Adenoviral vectors (Ad) have tremendous potential for CNS gene therapy approaches. Currently, the most common vectors utilize the Group C Ad5 serotype capsid proteins, which rely on the Coxsackievirus-Adenovirus receptor (CAR) to infect cells. However, these Ad5 vectors are unable to transduce many neuronal cell types that are dysfunctional in many CNS disorders. The human CD46 (hCD46) receptor is widely expressed throughout the human CNS and is the primary attachment receptor for many Ad serotypes. Therefore, to overcome the current limitations of Ad vectors to treat CNS disorders, we created chimeric first generation Ad vectors that utilize the hCD46 receptor. Using a \"humanized\" hCD46 mouse model, we demonstrate these Ad vectors transduce cerebellar cell types, including Purkinje cells, that are refractory to Ad5 transduction. Since Ad vector transduction properties are dependent on their capsid proteins, these chimeric first generation Ad vectors open new avenues for high-capacity helper-dependent adenovirus (HdAd) gene therapy approaches for cerebellar disorders and multiple neurological disorders.
摘要：
病毒载体基因治疗在治疗中枢神经系统（CNS）疾病方面具有巨大的前景。尽管腺相关病毒载体（AAV）已经取得了成功，它们的小包装容量限制了它们治疗许多CNS疾病的根本原因的效用。腺病毒载体（Ad）在CNS基因治疗方法中具有巨大的潜力。目前,最常见的载体利用C组Ad5血清型衣壳蛋白，依靠柯萨奇病毒-腺病毒受体（CAR）感染细胞。然而,这些Ad5载体不能转导在许多CNS疾病中功能失调的许多神经元细胞类型。人CD46(hCD46)受体在整个人CNS中广泛表达,并且是许多Ad血清型的主要附着受体。因此,为了克服目前Ad载体治疗中枢神经系统疾病的局限性，我们创建了利用hCD46受体的嵌合第一代Ad载体。使用“人源化”hCD46小鼠模型，我们证明了这些Ad载体转导小脑细胞类型，包括浦肯野细胞,对Ad5转导是难治的。由于Ad载体转导特性依赖于其衣壳蛋白，这些嵌合的第一代Ad载体为小脑疾病和多种神经系统疾病的高容量辅助依赖性腺病毒(HdAd)基因治疗方法开辟了新的途径.
