Relaxivity Contrast Imaging as Biomarker of Muscle Degeneration in ALS

弛豫对比成像作为 ALS 肌肉退化的生物标志物

• 批准号: 10783525
• 负责人: Christopher Chad Quarles
• 金额: $ 68.65万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10783525
• 关键词: ALS patients; Age; Amyotrophic Lateral Sclerosis; Antisense Oligonucleotide Therapy; Architecture; Atypia; Biological; Biological Markers; Cessation of life; Characteristics; Clinical; Clinical Markers; Clinical Trials; Data Analyses; Diameter; Disease; Disease Marker; Disease Progression; Edema; Exhibits; Fatty acid glycerol esters; Fiber; Foundations; Functional Imaging; Functional disorder; Goals; Health; Hospitals; Human; Image; Magnetic Resonance Imaging; Measures; Methods; Motor Cortex; Motor Neurons; Muscle; Muscular Atrophy; Nerve Degeneration; Neurologic; Neuromuscular Diseases; Pathologic; Patient Care; Patient-Centered Care; Patients; Performance; Pharmacodynamics; Phase II/III Clinical Trial; Process; Protocols documentation; Quality Control; Readiness; Reproducibility; Research; Respiratory physiology; Rodent Model; Sample Size; Spinal; Therapeutic Intervention; Upper Extremity; Validation; Vertebral column; biomarker discovery; biophysical properties; clinical heterogeneity; computer framework; contrast imaging; cost effective; data acquisition; density; design; drug development; drug discovery; early detection biomarkers; imaging approach; imaging biomarker; improved; innovation; multidisciplinary; muscle degeneration; muscle strength; nervous system disorder; neuroimaging; next generation; non-invasive imaging; novel; pre-clinical; rate of change; research clinical testing; response; response biomarker; sex; structural imaging; superoxide dismutase 1; treatment effect; treatment response

ABSTRACT Amyotrophic Lateral Sclerosis (ALS) is characterized by loss of spinal and cortical motor neurons, resulting in progressive muscle atrophy and eventually, death. The clinical heterogeneity and rapid progression of ALS continues to confound the identification of treatment response biomarkers. Currently, clinical trials (and practice) are forced to rely upon downstream indicators of disease status such as muscle strength, respiratory function and functional rating scales. Such measures, although validated, have a number of limitations. First, they have significant inter-rater variability. Second, the measures usually have relatively slow rates of change and thus, require months and even years to detect a treatment effect. These challenges underscore the unmet need for sensitive, reproducible, and non-invasive biomarkers of therapy response. To overcome these limitations, we propose to develop a non-invasive imaging approach, termed relaxivity contrast imaging (RCI). Unlike existing image-based biomarkers that reflect downstream changes in pathophysiology (e.g. T2 - edema, fat fraction), RCI is uniquely sensitive to myofiber architectural features (e.g. reduced fiber diameter and density, fiber atypia) exhibited by ALS patients. We hypothesize that RCI could serve as a pharmacodynamic/response biomarker to show efficacy of and biological response to therapeutic interventions in Phase 2/3 clinical trials of agents designed to slow or reverse neurodegeneration in ALS patients. To develop RCI, we will use a validated computational framework to systematically characterize the biophysical basis of RCI in the context of muscle degeneration and treatment response and use it to identify optimal acquisition and analysis strategies for applying RCI in a clinical trial. In preclinical rodent models of ALS, we will verify the association between RCI-based biomarkers and pathologic markers of muscle architecture and establish the utility of RCI-based biomarkers to detect response to therapy. In humans, we will characterize performance characteristics and repeatability of RCI protocols in healthy controls and ALS patients. To further refine RCI, we will establish quality control measures for RCI data acquisition and analysis and characterize age- and sex- dependent reference intervals of RCI-based biomarkers in healthy controls. Finally, we will establish the sensitivity of RCI-based biomarkers to disease progression in ALS patients and compare to other advanced image-based biomarkers and routine clinical markers of disease status. Ultimately, RCI has the potential to serve as a quantitative, myofiber-specific, image-based biomarker of early therapeutic response for ALS, potentially enabling smaller sample sizes, earlier Go/No Go decisions, more cost- effective clinical trials and, ultimately, improved patient care.

抽象的 肌萎缩性侧性硬化症（ALS）的特征是脊柱和皮质运动神经元的丧失， 导致进行性肌肉萎缩，并最终导致死亡。临床异质性和快速 ALS的进展继续使治疗反应生物标志物的识别混淆。 目前，临床试验（和实践）被迫依靠疾病状况的下游指标 例如肌肉力量，呼吸功能和功能等级量表。不过，这种措施 经过验证，有许多限制。首先，它们具有重大评价者的可变性。第二， 措施通常的变化率相对较慢，因此需要数月甚至数年才能 检测治疗效果。这些挑战强调了对敏感，可重现和 治疗反应的非侵入性生物标志物。为了克服这些局限性，我们建议开发 非侵入成像方法，称为松弛对比成像（RCI）。与现有的基于图像的不同 反映病理生理学下游变化的生物标志物（例如T2-水肿，脂肪分数），RCI为 对肌纤维建筑特征的独特敏感（例如，纤维直径和密度降低，纤维 ALS患者展示的Atypia）。我们假设RCI可以用作 药效/反应生物标志物表现出对治疗的功效和生物学反应的功效 旨在减慢或反向神经退行性的药物的2/3阶段临床试验中的干预措施 ALS患者。要开发RCI，我们将使用经过验证的计算框架进行系统的方式 在肌肉变性和治疗反应的背景下，表征RCI的生物物理基础 并使用它来确定在临床试验中应用RCI的最佳获取和分析策略。在 ALS的临床前啮齿动物模型，我们将验证基于RCI的生物标志物与 肌肉结构的病理标记，并建立基于RCI的生物标志物检测的实用性 对治疗的反应。在人类中，我们将表征性能特征和可重复性 健康对照和ALS患者中的RCI方案。为了进一步完善RCI，我们将建立质量 RCI数据获取和分析的控制措施，以及与年龄和性别相关的表征 基于RCI的生物标志物在健康对照中的参考间隔。最后，我们将建立灵敏度 基于RCI的生物标志物，促进ALS患者的疾病进展，并与其他晚期相比 基于图像的生物标志物和疾病状况的常规临床标记。最终，RCI有 有可能用作早期治疗的定量，基于图像的生物标志物 对ALS的响应，有可能实现较小的样本量，较早的行/没有决定，成本更高 - 有效的临床试验，最终改善了患者护理。