一种经过重新编程以结合人转铁蛋白受体的腺相关病毒衣壳介导全脑基因递送。
An AAV capsid reprogrammed to bind human Transferrin Receptor mediates brain-wide gene delivery.
作者信息
Huang Qin, Chan Ken Y, Lou Shan, Keyes Casey, Wu Jason, Botticello-Romero Nuria R, Zheng Qingxia, Johnston Jencilin, Mills Allan, Brauer Pamela P, Clouse Gabrielle, Pacouret Simon, Harvey John W, Beddow Thomas, Hurley Jenna K, Tobey Isabelle G, Powell Megan, Chen Albert T, Barry Andrew J, Eid Fatma-Elzahraa, Chan Yujia A, Deverman Benjamin E
机构信息
Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard; Cambridge, USA.
Department of Systems and Computer Engineering, Faculty of Engineering, Al-Azhar University; Cairo, Egypt.
出版信息
bioRxiv. 2023 Dec 22:2023.12.20.572615. doi: 10.1101/2023.12.20.572615.
Developing vehicles that efficiently deliver genes throughout the human central nervous system (CNS) will broaden the range of treatable genetic diseases. We engineered an AAV capsid, BI-hTFR1, that binds human Transferrin Receptor (TfR1), a protein expressed on the blood-brain barrier (BBB). BI-hTFR1 was actively transported across a human brain endothelial cell layer and, relative to AAV9, provided 40-50 times greater reporter expression in the CNS of human knock-in mice. The enhanced tropism was CNS-specific and absent in wild type mice. When used to deliver , mutations of which cause Gaucher disease and are linked to Parkinson's disease, BI-hTFR1 substantially increased brain and cerebrospinal fluid glucocerebrosidase activity compared to AAV9. These findings establish BI-hTFR1 as a promising vector for human CNS gene therapy.
开发能够在整个人类中枢神经系统（CNS）中有效递送基因的载体，将拓宽可治疗的遗传疾病范围。我们设计了一种腺相关病毒（AAV）衣壳BI-hTFR1，它能结合人转铁蛋白受体（TfR1），这是一种在血脑屏障（BBB）上表达的蛋白质。BI-hTFR1能被主动转运穿过人脑内皮细胞层，并且相对于AAV9，在人基因敲入小鼠的中枢神经系统中报告基因的表达提高了40到50倍。这种增强的嗜性是中枢神经系统特异性的，在野生型小鼠中不存在。当用于递送导致戈谢病且与帕金森病相关的突变基因时，与AAV9相比，BI-hTFR1显著提高了大脑和脑脊液中的葡萄糖脑苷脂酶活性。这些发现表明BI-hTFR1是一种有前景的人类中枢神经系统基因治疗载体。
Zotero 插件