Trial Readiness and Endpoint Assessment in LGMDR1 (TREATing-LGMDR1)

该项目的总体目标是为肢带型肌营养不良症R1（LGMDR 1）开发可靠有效的临床结局评估（COA）和生物标志物，以加速治疗开发。LGMDR 1是LGMD的常染色体隐性形式，由于肌肉结构基因CAPN 3的功能丧失。这种功能的丧失会导致肩部和臀部肌肉的进行性虚弱，从而导致进行性残疾，包括失去截肢或维持工作的能力。目前还没有FDA批准的LGMDR 1治疗方法，这代表了一个巨大的未满足的医疗需求。LGMDR 1适用于基因替代疗法;近年来，系统性基因疗法已被批准用于脊髓性肌萎缩症，并正在开发LGMDR 4。至少有五家公司正在开发针对LGMDR 1的基因靶向疗法或再生医学方法，这造成了一种局面，即治疗开发已经超出了我们为临床试验做准备的能力。本研究的基本原理是，根据广泛接受的相关疾病功能评估修改的LGMD（NSAID）的NorthStar动态评估需要作为LGMDR 1的主要终点进行验证。考虑到病情的缓慢进展性质，我们还预计，早期治疗试验需要生物标志物，如肌肉脂肪分数，以提供早期效应信号。我们提出了以下具体目的：1）验证NSAID作为LGMDR 1的主要终点; 2）验证定量肌肉MRI作为LGMDR 1的监测生物标志物。为了实现我们的目标，我们计划利用现有的LGMD临床研究网络，在我们的LGMD研究网络的12个站点对100名临床受影响的、非卧床的和遗传定义的LGMDR 1个体进行为期24个月的纵向观察研究。我们假设NSAD将适合多中心培训，可靠，与患者确定的疾病影响领域相关，并可用于即将进行的临床试验的功效和样本量规划。肌肉脂肪分数可能在NSAID变化之前显示进展。结合起来，我们将对疾病进展进行建模，以确定NSAID的评分范围，从而确定最佳治疗试验人群。在本研究完成时，我们将验证NSAID作为LGMDR 1的主要终点;验证肌肉脂肪分数作为LGMDR 1的理想生物标志物;建立临床试验特征，包括入选/排除标准、样本量和治疗试验的临床重要差异。鉴于LGMDR 1治疗开发的重大进展，迫切需要为该人群开发适当的COA和生物标志物。

The overall goal of this project is to develop reliable and valid clinical outcome assessments (COAs) and biomarkers for limb girdle muscular dystrophy R1 (LGMDR1) to hasten therapeutic development. LGMDR1 is an autosomal recessive form of LGMD due to a loss of function in muscle structural gene CAPN3. This loss of function leads to progressive weakness of the shoulder and hip girdle muscles and therefore progressive disability, including loss of ambulation or the ability to maintain a job. There are no FDA approved treatments for LGMDR1, which represents a large unmet medical need. LGMDR1 is amenable to gene replacement therapies; and in recent years, a systemic gene therapy has been approved for spinal muscular atrophy and is in development for LGMDR4. At least five companies have gene-targeted therapies or regenerative medicine approaches in development for LGMDR1, creating a situation where therapeutic development has outstripped our ability to prepare for clinical trials. The rationale for this study is that the NorthStar ambulatory assessment for LGMD (NSAD), modified from a widely accepted functional assessment in a related disorder, requires validation as a primary endpoint in LGMDR1. Given the slowly progressive nature of the condition, we also anticipate that a biomarker, such as muscle fat fraction, is required for early phase therapeutic trials to provide an early signal of effect. We propose the following Specific Aims: 1) To validate the NSAD as a primary endpoint for LGMDR1; and 2) To validate quantitative muscle MRI as a monitoring biomarker in LGMDR1. To achieve our aims, we plan to leverage an existing LGMD Clinical Research Network to conduct a 24-month longitudinal observational study of 100 clinically affected, ambulatory and genetically defined LGMDR1 individuals at 12 sites on our LGMD Research Network. We hypothesize that the NSAD will be amenable to multi-site training, reliable, related to patient-identified areas of disease impact, and useful for power and sample size planning for forthcoming clinical trials. The muscle fat fraction is likely to demonstrate progression in advance of change on the NSAD. Combined, we will model disease progression to define the range of scores on the NSAD that would define the optimal therapeutic trial population. At the completion of this study, we will have validated the NSAD as a primary endpoint for LGMDR1; validated muscle fat fraction as an ideal biomarker for LGMDR1; established the clinical trial characteristics, including inclusion/exclusion criteria, sample size, and clinically important difference for therapeutic trials. Given the significant progress in therapeutic development for LGMDR1, the development of appropriate COAs and biomarkers for this population is an urgent need.