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.

中文翻译：

---

重新编程结合人转铁蛋白受体的 AAV 衣壳介导全脑基因传递


开发能够有效地将基因传递到整个人类中枢神经系统（CNS）的载体将扩大可治疗遗传疾病的范围。我们设计了一种腺相关病毒 (AAV) 衣壳 BI-hTFR1，它可以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 主动转运穿过人脑内皮细胞，并且相对于 AAV9，在人 TFRC 敲入小鼠的 CNS 中提供了 40-50 倍的报告基因表达。增强的趋向性是中枢神经系统特异性的，并且在野生型小鼠中不存在。当用于递送 GBA1（GBA1 的突变会导致戈谢病并与帕金森病相关）时，与 AAV9 相比，BI-hTFR1 显着增加了大脑和脑脊液葡萄糖脑苷脂酶活性。这些发现确立了 BI-hTFR1 作为人类 CNS 基因治疗的潜在载体。