Validation of structural MRI as a biomarker in Huntington's disease

描述（由申请人提供）：结构MRI可能有潜力作为HD症状前和症状前临床试验的生物标志物，因为有大量证据表明，纹状体萎缩可以在预测运动发病前23年使用MRI检测到，纹状体体积与运动和认知功能以及CAG重复长度呈负相关，并随着疾病进展而继续缩小。因此，当HD基因扩增的个体表现出临床症状时，纹状体体积减少了一半以上。如果在明显的临床症状出现之前给予神经保护治疗，可能会提供更有效的益处。挑战是在没有临床症状的情况下评估假定的神经保护作用，因此，MRI测量作为HD的生物标志物的发展对于评估神经保护疗法非常有价值。然而，要在临床试验中验证这些措施，需要证明它们会随着治疗而改变。RNA干扰（RNAi）正在成为治疗HD的强有力的候选策略，可能比目前的药物候选更有效。AAV-miRNA （AAV-mi2.4）被证明是安全的，并在N171-82Q HD小鼠中提供治疗效果。我们最近在HD小鼠模型中描述了脑容量随疾病进展的纵向变化。在目前的提案中，我们的目标是验证结构MRI测量作为响应RNAi治疗的生物标志物，并通过在HD小鼠模型中使用MRI测量与行为和病理评估相结合进一步评估沉默突变亨廷顿蛋白的治疗效果。具体目的1：我们将确定纵向MRI测量是否可以检测AAV-mi2.4对N171- 82Q HD小鼠脑萎缩的疗效。基线脑容量将通过MRI获得。将AAV-mi2.4 （RNAi）或AAV-hrGFP注射到小鼠纹状体中，通过MRI扫描结合无偏全自动全脑分割分析，纵向评估全脑、纹状体和新皮层的体积变化。小鼠灌注进行组织学分析。运动功能和体重将在同一时间点评估。特异性目的2：我们将通过结构MRI在N171-82Q HD小鼠中确定双等位基因特异性突变亨廷顿蛋白siRNA （PM3）的功效。我们假设等位基因特异性RNAi将在HD小鼠中提供可通过MRI检测到的有益效果。将aav等位基因特异性RNAi注入小鼠纹状体。纵向进行MRI扫描。将分析组织学数据与MRI数据的相关性。运动行为表现和体重将在同一时间点进行评估。本研究的目的是为结构MRI作为临床前研究中评估治疗效果的生物标志物提供原理证明。最终目标是为在人类HD的治疗试验中使用结构MRI和潜在的RNAi策略提供一个基本原理，以获得FDA的批准。

DESCRIPTION (provided by applicant): Structural MRI may have potential as a biomarker for both pre-symptomatic and symptomatic clinical trials for HD, because there is a wealth of evidence that striatal atrophy can be detected using MRI up to 23 years prior to predicted motor onset and that striatal volume is negatively correlated with motor and cognitive function and CAG repeat length, and continues to shrink along with disease progression. Thus by the time individuals with HD gene expansion show clinical symptoms, striatal volumes are reduced by more than half. Neuroprotective therapy might provide a more effective benefit if given before overt clinical symptoms. The challenge is to evaluate putative neuroprotection in the absence of clinical symptoms, therefore, the development of MRI measures as biomarkers for HD could be extremely valuable for the assessment of neuroprotective therapies. Validation of these measures for clinical trials, however, requires a demonstration that they change with treatment. RNA interference (RNAi) is emerging as a powerful candidate strategy for treating HD, perhaps potentially more effective than current pharmacological candidates. AAV-miRNA (AAV-mi2.4) was demonstrated to be safe, and provided therapeutic benefit in N171-82Q HD mice. We have recently characterized brain volumetric changes longitudinally along with disease progression in mouse models of HD. In the current proposal, we aim to validate structural MRI measures as biomarkers in response to RNAi treatment and further evaluate therapeutic efficacy of silencing mutant huntingtin by using MRI measures in tandem with behavioral and pathological assessments in an HD mouse model. Specific Aim 1: We will determine whether longitudinal MRI measurements can detect efficacy of AAV-mi2.4 on brain atrophy in N171- 82Q HD mice. Baseline brain volume will be obtained by MRI. AAV-mi2.4 (RNAi) or AAV-hrGFP will be injected into mouse striatum and MRI scans combined with unbiased automatic whole brain segmentation analysis will be used to evaluate volumetric changes of whole brain, striatum, and neocortex longitudinally. Mice will be perfused for histological analysis. Motor function and body weight will be assessed at same time points. Specific Aim 2: We will determine the efficacy of a duplex allele-specific mutant huntingtin siRNA (PM3) by structural MRI in N171-82Q HD mice. We hypothesize that allele-specific RNAi will provide beneficial effects that can be detected by MRI measures in HD mice. AAV-allele-specific RNAi will be injected into mouse striatum. MRI scans will be performed longitudinally. Correlation between histology data and MRI data will be analyzed. Motor behavioral performance and body weight will be assessed at the same time points. The goal of this study is to provide proof-of-principle for structure MRI as a biomarker to evaluate therapeutic efficacy in preclinical studies. The ultimate goal is to provide a rationale for the use of structural MRI and potentially RNAi strategy in therapeutic trials of human HD for FDA approval. PUBLIC HEALTH RELEVANCE: Neuroprotective therapy might provide a more effective benefit if given before overt clinical symptoms. The development of MRI measures as biomarkers for HD could be extremely valuable for the assessment of neuroprotective therapies. The goal of this study is to provide proof-of-principle for structure MRI as a biomarker to evaluate therapeutic efficacy in preclinical studies.