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

基于非侵入性棒状能量景观生物标志物减轻色素性视网膜炎

基本信息

批准号：
10733154
负责人：
BRUCE A. BERKOWITZ
金额：
$ 50.18万
依托单位：
WAYNE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-30 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10733154
关键词：
Acceleration Address Atrophic Biological Assay Biological Markers Blindness Cell Culture Techniques Cessation of life Clinic Clinical Treatment Cone Darkness Diet Disease Early Diagnosis Ecosystem Electron Microscopy Etiology Evolution Experimental Models Exposure to Friends Functional disorder Future Genes Genetic Histologic Hour Inherited Knowledge Light Measurement Measures Methylene blue Mitochondria Mouse Strains Mus Mutation Names Natural History Nuclear Hormone Receptors Onset of illness Optical Coherence Tomography Oxygen Consumption Pathogenicity Pathology Patient-Focused Outcomes Patients Performance Periodicity Prediction of Response to Therapy Public Health Receptor Gene Reporting Research Retinitis Pigmentosa Rod Shapes Signal Transduction Synthetic Progestogens Technology Testing Time Tissues Transducin Treatment Efficacy Treatment outcome Up-Regulation Vertebrate Photoreceptors Vision Wild Type Mouse alpha Subunit Transducin bench to bedside biomarker performance clinically relevant dark rearing experimental study human model imaging biomarker imaging modality improved improved outcome indexing innovation loss of function mutation mitochondrial dysfunction neuroprotection non-invasive imaging novel personalized management phosphodiesterase 6 phosphoric diester hydrolase photoreceptor degeneration postnatal prevent restoration retinal rods translational barrier

项目摘要

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.

项目摘要/摘要：色素性视网膜炎 (RP) 是一种导致无法治疗且无法治愈的疾病。不可逆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，实验模型的离体研究支持异常。线粒体表现是导致 RP 病理的常见致病条件。评估患者的此类线粒体异常是不可能的，并且单一疗法适用于所有情况不太可能改善结果患者多样性需要解决这些主要的知识差距。患者友好的、非侵入性的线粒体性能生物标志物。最近，我们发现了一种新的线粒体性能指标，该指标基于以下特征：在光学相干断层扫描 (OCT) 中可轻松识别内段椭球区 (ISez)。对野生型小鼠的首次同类研究表明，ISez 轮廓的形状从拉长的在低能量需求条件（亮）期间，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了电子的支持两种具有不同线粒体的小鼠品系的显微镜和耗氧率测量例如，对循环光饲养的 2 个月大的具有 α 突变的小鼠进行 OCT 检查。转导蛋白 1 (Gnat1rd17) 亚基表现出适度的杆损失，ISez 比正常情况更圆且速率更高与黑暗中相比耗氧量的增加，这是早期线粒体过度表现的生物标志物证据。此外，在出生后 (P) 第 23 天，杆状磷酸二酯酶 6b 基因发生突变的黑暗饲养小鼠 (Pde6brd10) 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，当 P23 黑暗饲养的 Pde6brd10 小鼠处于线粒体过度表现的生物标志物证据。暴露在室内光线下 1 小时，它们表现出比正常 ISez 形状更椭圆的形状，表明存在棒状物质这是值得注意的，因为 1 小时的光照并没有导致线粒体表现不佳。据报道，在持续黑暗的几天后，立即发生额外的视杆细胞死亡，加速视杆细胞损失。这些考虑因素表明 ISez 轮廓形状对杆的异常敏感。 ISez 剖面形状变化的自然历史。与循环光饲养的 Gnat1rd17 或 Pde6brd10 小鼠中视杆细胞萎缩的关系尚不清楚。我们的工作假设是恢复我们的线粒体性能生物标志物（ISez 配置文件）形状）到野生型样水平可预测实验性 IRD 中的促生存治疗结果。研究引入了一种创新且临床相关的成像生物标志物，即 ISez 轮廓形状，用于评估 RP/IRD 恢复 ISez 轮廓形状至正常的治疗效果。最终有望防止 IRD 患者失明。