研究人员设计了一种腺相关病毒（AAV）衣壳BI-hTFR1，它能与人转铁蛋白受体（TfR1）结合，TfR1是一种在血脑屏障（BBB）上表达的蛋白质。BI-hTFR1可在人脑内皮细胞中主动转运，与AAV9相比，它在人TFRC基因敲入小鼠CNS中的报告表达量提高了40-50倍。这种增强的趋向性是CNS特异性的，在野生型小鼠中不存在。
当BI-hTFR1用于递送GBA1时（GBA1突变会导致戈谢病并与帕金森病有关），与AAV9相比，BI-hTFR1大大提高了脑和脑脊液葡萄糖脑苷脂酶的活性。这些发现使BI-hTFR1成为人类CNS基因治疗的潜在载体。
研究人员表示，开发能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遗传疾病的范围。
附：英文原文
Title: An AAV capsid reprogrammed to bind human transferrin receptor mediates brain-wide gene delivery
Author: Qin Huang, Ken Y. Chan, Jason Wu, Nuria R. Botticello-Romero, Qingxia Zheng, Shan Lou, Casey Keyes, Alexander Svanbergsson, Jencilin Johnston, Allan Mills, Chin-Yen Lin, Pamela P. Brauer, Gabrielle Clouse, Simon Pacouret, John W. Harvey, Thomas Beddow, Jenna K. Hurley, Isabelle G. Tobey, Megan Powell, Albert T. Chen, Andrew J. Barry, Fatma-Elzahraa Eid, Yujia A. Chan, Benjamin E. Deverman
Issue&Volume: 2024-05-16
Abstract: 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 (BBB). BI-hTFR1 was actively transported across human brain endothelial cells and, relative to AAV9, provided 40–50 times greater reporter expression in the CNS of human TFRC knock-in mice. The enhanced tropism was CNS-specific and absent in wild type mice. When used to deliver GBA1, 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 potential vector for human CNS gene therapy.
DOI: adm8386
Source: https://www.science.org/doi/10.1126/science.adm8386