PDF(Pubmed)
Abstract：
Retinitis pigmentosa (RP) is a heterogeneous disease and the main cause of vision loss within the group of inherited retinal diseases (IRDs). IRDs are a group of rare disorders caused by mutations in one or more of over 280 genes which ultimately result in blindness. Modifier genes play a key role in modulating disease phenotypes, and mutations in them can affect disease outcomes, rate of progression, and severity. Our previous studies have demonstrated that the nuclear hormone receptor 2 family e, member 3 (Nr2e3) gene reduced disease progression and loss of photoreceptor cell layers in RhoP23H-/- mice. This follow up, pharmacology study evaluates a longitudinal NR2E3 dose response in the clinically relevant heterozygous RhoP23H mouse. Reduced retinal degeneration and improved retinal morphology was observed 6 months following treatment evaluating three different NR2E3 doses. Histological and immunohistochemical analysis revealed regions of photoreceptor rescue in the treated retinas of RhoP23H+/- mice. Functional assessment by electroretinogram (ERG) showed attenuated photoreceptor degeneration with all doses. This study demonstrates the effectiveness of different doses of NR2E3 at reducing retinal degeneration and informs dose selection for clinical trials of RhoP23H-associated RP.
摘要：
视网膜色素变性（RP）是遗传性视网膜疾病（IRD）中的一种异质性疾病，是导致视力丧失的主要原因。IRD是一组罕见的疾病，由280多个基因中的一个或多个突变引起，最终导致失明。修饰基因在调节疾病表型中起关键作用，它们的突变会影响疾病的结果，进展速度,和严重性。我们以前的研究已经证明，核激素受体2家族e，成员3（Nr2e3）基因减少了RhoP23H-/-小鼠的疾病进展和感光细胞层的损失。这个后续,药理学研究评估了临床相关杂合RhoP23H小鼠的纵向NR2E3剂量反应。在评估三种不同NR2E3剂量的治疗后6个月观察到减少的视网膜变性和改善的视网膜形态。组织学和免疫组织化学分析揭示了RhoP23H+/-小鼠的治疗视网膜中的光感受器拯救区域。通过视网膜电图（ERG）进行的功能评估显示，所有剂量的光感受器变性均减弱。这项研究证明了不同剂量的NR2E3在减少视网膜变性方面的有效性，并为RhoP23H相关RP的临床试验提供了剂量选择。
