PDF(Pubmed)
Abstract：
Mucolipidosis IV (MLIV) is a rare, autosomal recessive, lysosomal disease characterized by intellectual disability, motor deficits, and progressive vision loss. Using adeno-associated vector 9 (AAV9) and AAV-PHP.B as delivery vectors, we previously demonstrated the feasibility of modifying disease course in a mouse model of MLIV by the human MCOLN1 gene transfer. Here, using a primate-enabling capsid AAV.CPP.16 (CPP16), we constructed a new, clinic-oriented MCOLN1 gene expression vector and demonstrated its efficacy in the preclinical model of MLIV. Systemic administration of CPP16-MCOLN1 in adult symptomatic Mcoln1 -/- mice at a dose of 1e12 vg per mouse resulted in MCOLN1 expression in the brain and peripheral tissues, alleviated brain pathology, rescued neuromotor function, and completely prevented paralysis. Notable expression of MCOLN1 transcripts was also detected in the retina of the mouse, which had exhibited significant degeneration at the time of the treatment. However, no increase in retinal thickness was observed after gene therapy treatment. Our results suggest a new AAV-based systemic gene replacement therapy for the treatment of MLIV that could be translated into clinical studies.
摘要：
粘脂症IV（MLIV）是一种罕见的，常染色体隐性遗传,以智力障碍为特征的溶酶体疾病，运动障碍,和渐进性视力丧失。使用腺相关载体9(AAV9)和AAV-PHP。B作为传递载体，我们先前证明了通过人MCLN1基因转移在MLIV小鼠模型中改变病程的可行性.这里,使用灵长类动物使能衣壳AAV。CPP.16(CPP16),我们建造了一个新的，面向临床的MCLN1基因表达载体，并证明其在MLIV临床前模型中的功效。在成年症状Mcoln1-/-小鼠中以每只小鼠1e12vg的剂量全身施用CPP16-MCLN1导致MCLN1在大脑和外周组织中表达，减轻脑部病理，获救的神经运动功能，完全避免瘫痪。在小鼠的视网膜中也检测到MCLN1转录物的显著表达，在治疗时表现出明显的变性。然而,在基因治疗治疗后,未观察到视网膜厚度增加.我们的结果表明一种新的基于AAV的系统基因替代疗法，用于治疗MLIV，可以转化为临床研究。
