Dutch-type cerebral amyloid angiopathy (D-CAA) is a monogenic form of cerebral amyloid angiopathy and is inherited in an autosomal dominant manner. The disease is caused by a point mutation in exon 17 of the amyloid precursor protein (APP) gene that leads to an amino acid substitution at codon 693. The mutation is located within the amyloid beta (Aβ) domain of APP, and leads to accumulation of toxic Aβ peptide in and around the cerebral vasculature. We have designed an antisense oligonucleotide (AON) approach that results in skipping of exon 17, generating a shorter APP isoform that lacks part of the Aβ domain and the D-CAA mutation. We demonstrate efficient AON-induced skipping of exon 17 at RNA level and the occurrence of a shorter APP protein isoform in three different cell types. This resulted in a reduction of Aβ40 in neuronally differentiated, patient-derived induced pluripotent stem cells. AON-treated wild-type mice showed successful exon skipping on RNA and protein levels throughout the brain. These results illustrate APP splice modulation as a promising therapeutic approach for D-CAA.

中文翻译：

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反义寡核苷酸诱导的淀粉样前体蛋白剪接调节作为荷兰型脑淀粉样血管病的治疗方法

荷兰型脑淀粉样血管病（D-CAA）是脑淀粉样血管病的一种单基因形式，以常染色体显性遗传方式遗传。该病是由淀粉样前体蛋白（APP ）的第 17 外显子的点突变引起的。) 基因，导致密码子 693 处的氨基酸取代。该突变位于 APP 的淀粉样蛋白 β (Aβ) 结构域内，并导致有毒 Aβ 肽在脑血管系统内和周围积累。我们设计了一种反义寡核苷酸 (AON) 方法，该方法导致跳过外显子 17，生成缺少部分 Aβ 结构域和 D-CAA 突变的较短 APP 同种型。我们证明了在 RNA 水平上有效的 AON 诱导的外显子 17 跳跃以及在三种不同细胞类型中出现较短的 APP 蛋白同种型。这导致神经元分化的、患者来源的诱导多能干细胞中的 Aβ40 减少。AON 处理的野生型小鼠在整个大脑的 RNA 和蛋白质水平上显示出成功的外显子跳跃。这些结果说明APP剪接调制作为一种有前途的 D-CAA 治疗方法。