Zin Emilia A, Han Daisy, Tran Jennifer, Morisson-Welch Nikolas, Visel Meike, Kuronen Mervi, Flannery John G
Vision Science Group, School of Optometry, UC Berkeley, Berkeley, CA 94720, USA.
Department of Integrative Biology, UC Berkeley, Berkeley, CA 94720, USA.
Mol Ther Methods Clin Dev. 2021 May 29;22:40-51. doi: 10.1016/j.omtm.2021.05.009. eCollection 2021 Sep 10.
Neuronal ceroid lipofuscinosis (NCL) is a family of neurodegenerative diseases caused by mutations to genes related to lysosomal function. One variant, CNL11, is caused by mutations to the gene encoding the protein progranulin, which regulates neuronal lysosomal function. Absence of progranulin causes cerebellar atrophy, seizures, dementia, and vision loss. As progranulin gene therapies targeting the brain are developed, it is advantageous to focus on the retina, as its characteristics are beneficial for gene therapy development: the retina is easily visible through direct imaging, can be assessed through quantitative methods , and requires smaller amounts of adeno-associated virus (AAV). In this study we characterize the retinal degeneration in a progranulin knockout mouse model of CLN11 and study the effects of gene replacement at different time points. Mice heterologously expressing progranulin showed a reduction in lipofuscin deposits and microglia infiltration. While mice that receive systemic AAV92YF-scCAG-PGRN at post-natal day 3 or 4 show a reduction in retina thinning, mice injected intravitreally at months 1 and 6 with AAV2.7m8-scCAG-PGRN exhibit no improvement, and mice injected at 12 months of age have thinner retinas than do their controls. Thus, delivery of progranulin proves to be time sensitive and dependent on route of administration, requiring early delivery for optimal therapeutic benefit.
神经元蜡样脂褐质沉积症（NCL）是一类由与溶酶体功能相关的基因突变引起的神经退行性疾病。其中一种变体CLN11是由编码前颗粒蛋白的基因突变引起的，该蛋白调节神经元溶酶体功能。前颗粒蛋白的缺失会导致小脑萎缩、癫痫、痴呆和视力丧失。随着针对大脑的前颗粒蛋白基因疗法的发展，将重点放在视网膜上是有利的，因为其特性有利于基因疗法的开发：视网膜通过直接成像很容易看到，可以通过定量方法进行评估，并且需要较少数量的腺相关病毒（AAV）。在本研究中，我们对CLN11的前颗粒蛋白敲除小鼠模型中的视网膜变性进行了表征，并研究了不同时间点基因替代的效果。异源表达前颗粒蛋白的小鼠脂褐质沉积和小胶质细胞浸润减少。虽然在出生后第3天或第4天接受全身AAV92YF - scCAG - PGRN的小鼠视网膜变薄有所减少，但在1个月和6个月时玻璃体内注射AAV2.7m8 - scCAG - PGRN的小鼠没有改善，而在12个月大时注射的小鼠视网膜比其对照组更薄。因此，前颗粒蛋白的递送被证明对时间敏感且取决于给药途径 需要早期递送以获得最佳治疗效果。
