Mitigating retinitis pigmentosa based on a non-invasive rod energy-landscape biomarker

项目摘要/摘要：视网膜色素变性（RP）是一种疾病，导致无法治愈， 不可逆转的视锥细胞死亡和失明无数的功能丧失突变，包括转导蛋白1或 磷酸二酯酶6基因是RP的基础基因。来自实验模型的离体研究支持异常 线粒体表现为导致RP病理的常见致病性病症。然而，在这方面， 评估患者的这种线粒体异常是不可能的， 不太可能改善患者的多样性。解决这些重大的知识差距将需要 线粒体性能的患者友好的非侵入性生物标志物。 最近，我们发现了一种新的线粒体性能指数， 在光学相干断层扫描（OCT）中容易识别的内段椭圆带（ISez）。我们 在野生型小鼠中进行的首次同类研究表明，ISez曲线的形状从细长的 在低能量需求条件（亮）期间变圆到在高能量需求条件（暗）期间变圆。 ISez轮廓形状变化的潜在线粒体病因学得到电子显微镜的支持。 在两种具有不同线粒体的小鼠品系中进行显微镜和耗氧率测量 活动例如，OCT检查循环光饲养的2个月大的小鼠，其α基因突变， 转导素1亚基（Gnat 1 rd 17）表现出适度的视杆细胞丢失，ISez圆于正常值， 氧消耗比在黑暗中，生物标志物证据早期线粒体过度表现。 此外，在出生后（P）第23天，在视杆细胞磷酸二酯酶6 b基因突变的黑暗饲养小鼠， （Pde 6 brd 10）在黑暗中检查时显示出适度的杆损失以及比正常更圆的ISez， 线粒体过度表现的生物标志物证据。当P23黑暗饲养的Pde 6 brd 10小鼠被 暴露于室内光1小时，它们显示出比正常ISez形状更椭圆的形状，表明杆 线粒体表现不佳。这是值得注意的，因为，虽然1小时的光没有造成 立即额外的棒死亡，加速棒损失据报道发生在持续黑暗后几天- 养育这些考虑表明，ISez剖面形状对棒中的异常敏感 能量景观之前，后来棒损失。ISez剖面形状变化的自然历史， 与周期性光照饲养的Gnat 1 rd 17或Pde 6 brd 10小鼠视杆萎缩有关。 我们的工作假设是，恢复我们的线粒体性能生物标志物（ISez概况）， 形状）至野生型样水平预测实验IRD中的促存活治疗结果。这些 研究引入了一种创新的和临床相关的成像生物标志物，ISez轮廓形状， 评估RP/IRD的治疗效果。使ISez轮廓形状恢复正常的疗法有 最终有望防止IRD患者失明。

Project Summary / Abstract: Retinitis pigmentosa (RP) is a disease that leads to untreatable and irreversible cone death and blindness. A myriad of loss-of-function mutations, including in transducin 1 or phosphodiesterase 6 genes, underlie RP. Ex vivo studies from experimental models support abnormal mitochondria performance as a common pathogenic condition leading to RP pathology. However, evaluating such mitochondrial abnormalities in patients is not possible and a one-therapy-fits-all approach is unlikely to improve outcomes patient diversity. Addressing these major knowledge gaps will require a patient-friendly, non-invasive biomarker of mitochondria performance. Recently, we discovered a novel index of mitochondria performance based on a feature that is readily identifiable in optical coherence tomography (OCT), the inner segment ellipsoid zone (ISez). Our first-in-kind studies in wild-type mice show that the shape of the ISez profile changes from elongated during a low energy demand condition (light) to rounder during a high energy demand condition (dark). The underlying mitochondria etiology of the change in ISez profile shape is supported by electron microscopy and oxygen consumption rate measurements in two mice strains with distinct mitochondria activity. For example, OCT examination of cyclic-light reared 2-month-old mice with a mutation in the α subunit of transducin 1 (Gnat1rd17) shows modest rod loss with a rounder-than-normal ISez and higher rate of oxygen consumption than in the dark, biomarker evidence for early mitochondria overperformance. Also, at postnatal (P) day 23, dark-reared mice with a mutation in the rod phosphodiesterase 6b gene (Pde6brd10) show modest rod loss together with rounder-than-normal ISez when examined in the dark, biomarker evidence for mitochondria overperformance. When P23 dark-reared Pde6brd10 mice are exposed to room light for 1 hour they showed a more-elliptical-than-normal ISez shape suggesting rod mitochondria underperformance. This is notable because, whilst the 1 hour of light did not cause immediate additional rod death, accelerated rod loss reportedly occurs days later after continued dark- rearing. These considerations show that the ISez profile shape is sensitive to abnormalities in the rod energy landscape that precede later rod loss. The natural history of change of the ISez profile shape as it relates to rod atrophy in cyclic-light reared Gnat1rd17 or Pde6brd10 mice is unknown. Our working hypothesis is that restoring our mitochondria performance biomarker (the ISez profile shape) to wild-type-like levels predicts pro-survival treatment outcomes in experimental IRD. These studies introduce an innovative and clinically relevant imaging biomarker, the ISez profile shape, for assessing treatment efficacy in RP/IRD. Therapies that restore the ISez profile shape to normal are ultimately expected to prevent loss of sight in patients with IRD.