PDF(Pubmed)
Abstract：
Nicotinamide nucleotide adenylyltransferase 1 (NMNAT1) is a ubiquitously expressed enzyme involved in nuclear NAD+ production throughout the body. However, mutations in the NMNAT1 gene lead to retina-specific disease with few reports of systemic effects. We have previously demonstrated that AAV-mediated gene therapy using self-complementary AAV (scAAV) to ubiquitously express NMNAT1 throughout the retina prevents retinal degeneration in a mouse model of NMNAT1-associated disease. We aimed to develop a better understanding of the cell types in the retina that contribute to disease pathogenesis in NMNAT1-associated disease, and to identify the cell types that require NMNAT1 expression for therapeutic benefit. To achieve this goal, we treated Nmnat1V9M/V9M mice with scAAV using cell type-specific promoters to restrict NMNAT1 expression to distinct retinal cell types. We hypothesized that photoreceptors are uniquely vulnerable to NAD+ depletion due to mutations in NMNAT1. Consistent with this hypothesis, we identified that treatments that drove NMNAT1 expression in the photoreceptors led to preservation of retinal morphology. These findings suggest that gene therapies for NMNAT1-associated disease should aim to express NMNAT1 in the photoreceptor cells.
摘要：
烟酰胺核苷酸腺苷酸转移酶1（NMNAT1）是一种广泛表达的酶，涉及整个身体的核NAD产生。然而,NMNAT1基因的突变导致视网膜特异性疾病,系统效应的报道很少.我们先前已经证明，使用自我互补AAV（scAAV）在整个视网膜中普遍表达NMNAT1的AAV介导的基因治疗可以防止NMNAT1相关疾病的小鼠模型中的视网膜变性。我们的目的是更好地了解NMNAT1相关疾病中视网膜中有助于疾病发病机理的细胞类型，并鉴定需要NMNAT1表达以获得治疗益处的细胞类型。为了实现这一目标,我们使用细胞类型特异性启动子用scAAV处理Nmnat1V9M/V9M小鼠,以将NMNAT1表达限制在不同的视网膜细胞类型中.我们假设，由于NMNAT1中的突变，光感受器对NAD消耗具有独特的脆弱性。与这个假设一致，我们发现驱动NMNAT1在光感受器中表达的治疗导致视网膜形态的保留.这些发现表明，NMNAT1相关疾病的基因治疗应旨在在感光细胞中表达NMNAT1。
