AAV gene transfer delays disease onset in a TPP1-deficient canine model of the late infantile form of Batten disease
AAV gene transfer delays disease onset in a TPP1-deficient canine model of the late infantile form of Batten disease
复制标题
AAV 基因转移可延缓 TPP1 缺失的晚期婴儿型巴顿病犬模型的发病时间
DOI：
10.1126/scitranslmed.aac6191
复制
发表时间：
2015-11-11
影响因子：
17.1
通讯作者：
Davidson, Beverly L.
中科院分区：
文献类型：
--
作者：
Katz, Martin L.;Tecedor, Luis;Davidson, Beverly L.
最常见的儿童神经退行性疾病晚期婴儿神经元蜡样质脂褐质沉积症（也称为Batten病）是由可溶性溶酶体酶三肽基肽酶1（TPP1）基因突变引起的缺乏引起的。我们测试了TPP1基因转移到室管膜，脑室系统的上皮衬里，在TPP1缺陷的狗是否会有治疗上的好处。一次性施用表达犬TPP1的重组腺相关病毒（rAAV）（rAAV.caTPP1）导致TPP1主要在室管膜细胞中的高表达，并将酶分泌到脑脊液中，从而导致临床益处。用rAAV.caTPP1治疗的患病狗显示出延迟临床体征和疾病进展的发作、防止认知下降和延长寿命。通过免疫染色和酶测定，重组蛋白在整个脑和脊髓中是明显的，具有疾病的神经病理学特征的校正。在天然存在的TPP1缺陷犬模型中的这项研究突出了心室衬里细胞的AAV转导的效用，以实现重组蛋白在中枢神经系统中的广泛分布和治疗益处的稳定分泌。
The most common form of the childhood neurodegenerative disease late infantile neuronal ceroid lipofuscinosis (also called Batten disease) is caused by deficiency of the soluble lysosomal enzyme tripeptidyl peptidase 1 (TPP1) resulting from mutations in the TPP1 gene. We tested whether TPP1 gene transfer to the ependyma, the epithelial lining of the brain ventricular system, in TPP1-deficient dogs would be therapeutically beneficial. A one-time administration of recombinant adeno-associated virus (rAAV) expressing canine TPP1 (rAAV.caTPP1) resulted in high expression of TPP1 predominantly in ependymal cells and secretion of the enzyme into the cerebrospinal fluid leading to clinical benefit. Diseased dogs treated with rAAV.caTPP1 showed delays in onset of clinical signs and disease progression, protection from cognitive decline, and extension of life span. By immunostaining and enzyme assay, recombinant protein was evident throughout the brain and spinal cord, with correction of the neuropathology characteristic of the disease. This study in a naturally occurring canine model of TPP1 deficiency highlights the utility of AAV transduction of ventricular lining cells to accomplish stable secretion of recombinant protein for broad distribution in the central nervous system and therapeutic benefit.