Novel Neuronal Transport Mechanisms of Lyosomal Enzymes

描述（由申请方提供）：由于大脑中蓄积物质导致的认知缺陷可能是与溶酶体蓄积病相关的最严重临床体征。CNS缺陷也难以治疗。我们最近将AAV载体直接注射到粘多糖沉积症VII型（MPS VII）小鼠模型的眼玻璃体中。在视网膜和视神经中观察到高水平的GUSB活性。我们还在NTS VII小鼠的大脑中发现了GUSB活动。GUSB活性主要在视觉束中检测到，特别是外侧膝状体和上级丘。有趣的是，溶酶体储存物质的减少超出了视觉系统，进入海马和大脑皮层。因此，这种方法可以代表将治疗水平的溶酶体酶递送到脑中的侵入性较小的方法。本项目的目标是确定MPS VII小鼠和犬模型中野生型和改良GUSB的分布以及组织病理学校正的程度。我们还将确定溶酶体酶从眼睛到大脑的运输与储存减少是否是另一种溶酶体储存疾病的共同点。我们将通过以下具体目标来实现这些目标。1)我们将确定天然和修饰的GUSB的分布，以及玻璃体内注射基因转移载体后MPS VII小鼠模型CNS中溶酶体贮积减少的程度。2)我们将确定天然和修饰的GUSB的分布，以及玻璃体内注射基因转移载体后MPS VII犬模型CNS中溶酶体贮积减少的程度。3)我们将确定棕榈酰蛋白硫酯酶1的分布和对婴儿神经元蜡样质脂褐质沉积症小鼠模型玻璃体内注射基因转移载体后大脑中溶酶体蓄积的影响。

DESCRIPTION (provided by applicant): Cognitive deficits due to the accumulation of storage material in the brain can be the most severe clinical signs associated with lysosomal storage diseases. The CNS defects are also difficult to treat. We recently injected an AAV vector directly into the vitreous of the eye in the murine model of mucopolysaccharidosis type VII (MPS VII). High levels of GUSB activity were observed in the retina and in the optic nerve. We also discovered GUSB activity in the brains of NTS VII mice. GUSB activity was detected primarily in the visual tracts, specifically the lateral geniculate and superior colliculus. Interestingly, the reduction of lysosomal storage material extended beyond the visual system and into the hippocampus and cerebral cortex. Therefore, this approach may represent a less invasive method of delivering therapeutic levels of a lysosomal enzyme into the brain. The goals of this project are to determine the distribution of wild type and modified GUSB and the extent of histopathologic correction in both the mouse and canine models of MPS VII. We will also determine if the transport of a lysosomal enzyme from the eye to the brain with a reduction of storage is common to another lysosomal storage disease. We will accomplish these goals with the following Specific Aims. 1) We will determine the distribution of both native and modified GUSB, and the extent of lysosomal storage reduction in the CNS of the murine model of MPS VII following intravitreal injection of a gene transfer vector. 2) We will determine the distribution of both native and modified GUSB, and the extent of lysosomal Storage reduction in the CNS of the canine model of MPS VII following intravitreal injection of a gene transfer vector. 3) We will determine the distribution of palmitoyl protein thioesterase 1 and the effect on lysosomal storage in the brain of the murine model of infantile neuronal ceroid lipofuscinosis following intravitreal injection of a gene transfer vector.