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)是一种导致无法治疗和 不可逆转的锥体死亡和失明。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，位于RP之下。实验模型的体外研究支持异常 线粒体表现为导致RP病理的一种常见致病状态。然而， 评估患者的这种线粒体异常是不可能的，而且是一种一刀切的方法 不太可能改善结果患者的多样性。解决这些主要的知识差距将需要 患者友好、非侵入性的线粒体性能生物标记物。 最近，我们发现了一种新的线粒体性能指数，它基于一个特征，即 内段椭球区(ISEZ)在光学相干断层扫描(OCT)中很容易辨认。我们的 对野生型小鼠的首次同类研究表明，ISEZ图谱的形状从拉长的 在低能量需求条件下(光)到在高能量需求条件下(黑暗)变圆。 ISEZ轮廓形状改变的线粒体病因学由电子支持 两个线粒体不同品系小鼠的显微镜和耗氧率测量 活动。例如，对2个月大的α突变的循环光饲养的小鼠进行OCT检查 转导蛋白1亚单位(Gnat1rd17)表现出适度的杆状损失，比正常的ISEZ更圆，比率更高 比在黑暗中耗氧量更大，这是早期线粒体表现超常的生物标志证据。 此外，在出生后(P)第23天，黑暗饲养的小鼠带有条状磷酸二酯酶6b基因的突变 (Pde6brd10)在黑暗中检查时，显示出适度的杆状损失以及比正常更圆的ISEZ， 线粒体表现优异的生物标志物证据。当P23暗饲养的Pde6brd10小鼠 暴露在室内光线下1小时，它们显示出比正常情况下更椭圆形的ISez形状，这表明它们是杆状的 线粒体表现不佳。值得注意的是，虽然1小时的光照不会导致 立即额外的杆死亡，据报道在持续黑暗的几天后发生加速杆丢失- 养育。这些考虑表明，ISEZ轮廓形状对杆中的异常很敏感 在后来的棒材损失之前的能源格局。伊塞兹剖面形状随时间变化的自然历史 与周期性光照饲养的Gnat1rd17或Pde6brd10小鼠的视杆萎缩有关尚不清楚。 我们的工作假设是，恢复我们的线粒体性能生物标记物(ISEZ图谱 形状)到野生型水平预测实验性IRD的有利于生存的治疗结果。这些 研究介绍了一种创新的和临床相关的成像生物标记物，ISEZ轮廓形状，用于 评价RP/IRD的治疗效果。将ISEZ轮廓形状恢复到正常状态的疗法有 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.