An AAV capsid reprogrammed to bind human Transferrin Receptor mediates brain-wide gene delivery.
An AAV capsid reprogrammed to bind human Transferrin Receptor mediates brain-wide gene delivery.
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重新编程的 AAV 衣壳可结合人转铁蛋白受体，介导全脑基因传递。
DOI：
10.1101/2023.12.20.572615
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Tobey,Isabel
中科院分区：
文献类型：
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作者：
Huang,Qin;Chan,KenY;Lou,Shan;Keyes,Casey;Wu,Jason;Botticello-Romero,NuriaR;Zheng,Qingxia;Johnston,Jencilin;Mills,Allan;Brauer,PamelaP;Clouse,Gabrielle;Pacouret,Simon;Harvey,JohnW;Beddow,Thomas;Hurley,JennaK;Tobey,Isabel
开发在整个人类中枢神经系统（CNS）中有效传递基因的载体将扩大可治疗的遗传疾病的范围。我们设计了一种腺相关病毒（AAV）衣壳，BI-hTFR 1，它结合人转铁蛋白受体（TfR 1），一种在血脑屏障上表达的蛋白质。BI-hTFR 1被主动转运穿过人脑内皮细胞，并且相对于AAV 9，在人TFRC敲入小鼠的CNS中提供了40至50倍的报告基因表达。增强的向性是CNS特异性的，在野生型小鼠中不存在。当用于递送GBA 1（其突变导致戈谢病并与帕金森病相关）时，与AAV 9相比，BI-hTFR 1显著增加了脑和脑脊液葡萄糖脑苷脂酶活性。这些发现确立了BI-hTFR 1作为人类CNS基因治疗的潜在载体。
Developing vehicles that efficiently deliver genes throughout the human central nervous system (CNS) will broaden the range of treatable genetic diseases. We engineered an adeno-associated virus (AAV) capsid, BI-hTFR1, that binds human transferrin receptor (TfR1), a protein expressed on the blood-brain barrier. BI-hTFR1 was actively transported across human brain endothelial cells and, relative to AAV9, provided 40 to 50 times greater reporter expression in the CNS of humanTFRCknockin mice. The enhanced tropism was CNS-specific and absent in wild-type mice. When used to deliverGBA1, mutations of which cause Gaucher disease and are linked to Parkinson’s disease, BI-hTFR1 substantially increased brain and cerebrospinal fluid glucocerebrosidase activity compared with AAV9. These findings establish BI-hTFR1 as a potential vector for human CNS gene therapy.