A brain microvasculature endothelial cell-specific viral vector with the potential to treat neurovascular and neurological diseases.
A brain microvasculature endothelial cell-specific viral vector with the potential to treat neurovascular and neurological diseases.
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DOI：
10.15252/emmm.201506078
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发表时间：
2016-06
影响因子：
11.1
通讯作者：
Trepel M
中科院分区：
文献类型：
--
作者：
Körbelin J;Dogbevia G;Michelfelder S;Ridder DA;Hunger A;Wenzel J;Seismann H;Lampe M;Bannach J;Pasparakis M;Kleinschmidt JA;Schwaninger M;Trepel M
基因治疗关键地依赖于将高转导效率与高度靶特异性结合的联合收割机，并且可以通过安全的静脉内途径施用的载体。缺乏合适的载体，特别是用于脑疾病的基因治疗的载体，是一个主要障碍。因此，我们应用腺相关病毒衣壳上展示的随机配体文库的体内筛选系统来选择用于治疗神经血管疾病的脑靶向载体。我们鉴定了一种衣壳变体，其对脑微血管内皮细胞表现出前所未有的特异性和持久的转导效率，作为选择的主要靶点。基于这种选择的病毒衣壳的治疗载体用于在单次静脉内注射后显著减弱患有色素失禁的小鼠的严重脑血管病理。此外，该选择系统的多功能性将使得有可能选择用于其他体内靶标的配体，而不需要预先鉴定潜在的靶标特异性受体。
Gene therapy critically relies on vectors that combine high transduction efficiency with a high degree of target specificity and that can be administered through a safe intravenous route. The lack of suitable vectors, especially for gene therapy of brain disorders, represents a major obstacle. Therefore, we applied an in vivo screening system of random ligand libraries displayed on adeno‐associated viral capsids to select brain‐targeted vectors for the treatment of neurovascular diseases. We identified a capsid variant showing an unprecedented degree of specificity and long‐lasting transduction efficiency for brain microvasculature endothelial cells as the primary target of selection. A therapeutic vector based on this selected viral capsid was used to markedly attenuate the severe cerebrovascular pathology of mice with incontinentia pigmenti after a single intravenous injection. Furthermore, the versatility of this selection system will make it possible to select ligands for additional in vivo targets without requiring previous identification of potential target‐specific receptors.