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

描述(申请人提供)：结构MRI可能作为HD无症状和有症状临床试验的生物标志物，因为有大量证据表明，使用MRI可以在预测的运动开始前23年检测到纹状体萎缩，并且纹状体体积与运动和认知功能以及CAG重复长度呈负相关，并随着疾病的进展而持续缩小。因此，当HD基因扩增的个体出现临床症状时，纹状体体积减少了一半以上。如果在出现明显的临床症状之前给予神经保护治疗，可能会提供更有效的好处。挑战是在没有临床症状的情况下评估可能的神经保护，因此，发展MRI方法作为HD的生物标记物对神经保护治疗的评估非常有价值。然而，临床试验对这些措施的验证需要证明它们会随着治疗的变化而改变。RNA干扰(RNAi)正在成为治疗HD的一种强有力的候选策略，可能比目前的药理学候选策略更有效。AAV-miRNA(AAV-mi2.4)被证明是安全的，并在N171-82Q HD小鼠中提供了治疗益处。我们最近在HD小鼠模型中表征了随着疾病进展而纵向的脑体积变化。在目前的提案中，我们的目标是验证结构MRI指标作为RNAi治疗反应的生物标记物的有效性，并通过在HD小鼠模型中使用MRI指标结合行为和病理评估来进一步评估沉默突变Huntingtin的治疗效果。具体目标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。基线脑体积将通过核磁共振获得。将AAV-mi2.4(RNAi)或AAV-hrGFP注射到小鼠纹状体，MRI扫描结合无偏全脑自动分割分析将评估整个大脑、纹状体和新皮质的纵向体积变化。小鼠将被灌流进行组织学分析。运动功能和体重将在同一时间点进行评估。特定目的2：我们将通过结构磁共振确定双重等位基因特异性突变体Huntingtin siRNA(PM3)在N171-82Q HD小鼠中的疗效。我们假设，等位基因特异的RNAi将提供可以通过核磁共振测量在HD小鼠中检测到的有益效果。将AAV等位基因特异性RNAi注射到小鼠纹状体内。核磁共振扫描将进行纵向扫描。将分析组织学数据和MRI数据之间的相关性。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磁共振作为生物标记物在临床前研究中评估治疗效果提供原则证据。最终目标是为在FDA批准的人类HD治疗试验中使用结构性MRI和潜在的RNAi策略提供理论基础。 与公共卫生相关：如果在出现明显的临床症状之前给予神经保护治疗，可能会提供更有效的益处。作为HD生物标志物的MRI措施的发展对于神经保护治疗的评估可能是非常有价值的。本研究的目的是为结构磁共振作为生物标记物在临床前研究中评估治疗效果提供原则证据。

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.