Biomarkers to enable ASO prevention trials in genetic prion disease carriers

人类Pron病是一种罕见的、异常迅速的、普遍致命的神经退行性疾病。尽管 目前无法治疗的所有普恩病毒疾病都遵循单一的分子机制，通过这种机制， 天然PrP由PrNP基因编码，错误折叠为致病构象。 这些所谓的Prion模版健康的PrP分子的构象破坏，推动了传播 普恩病毒和普恩病毒引起的神经毒性在整个大脑。作为Pron转化的必要底物， 天然PrP已经成为Pron病的一个有吸引力的治疗靶点。几十年的证据表明 天然PrP的减少是剂量依赖性的，对Pron病具有保护作用。完全淘汰赛总比分 预防疾病，动物和人类证据表明，PrP的减少应该是好的 被容忍了。鉴于这些有希望的概念证明，我们正在与Ionis PharmPharmticals合作 开发降低PrP的反义寡核苷酸(ASO)，通过靶向PrP RNA来降低大脑中的PrP 退化。初步的临床前研究表明，针对Prion蛋白的ASO有效地延长了患者的生存时间。 普恩病毒感染的动物，预防性治疗带来最大的好处。我们的初步约定 与FDA的合作表明，在无症状的Pron病突变携带者中进行的一级预防试验可能 降低脑脊液(CSF)中的PrP可能是加速治疗的可行替代终点 批准一种降低PrP的治疗方法。通过FDA的参与，以下三个目标将汇集关键 和时间敏感的数据使这条临床路径成为可能。1)评估短期受试者内测试-重测稳定性 无症状遗传性朊病毒病突变携带者和非携带者脑脊液PrP的检测。我们会 用技术验证的酶联免疫吸附试验确定重复捐献的脑脊液样本中PrP水平的短期稳定性 每隔2-4个月由遗传性普恩病毒携带者和对照组控制。2)确定两者之间的相关性 大鼠脑和脑脊液PrP基因敲除，以及脑PrP基因敲除与小鼠存活之间的关系。我们会 分析ASO处理的啮齿动物组织，以模拟脑和脑脊液PrP水平之间的关系，以及 脑PrP基因敲除与生存期延长的关系3)收集病理性生物标志物数据 评估在有症状的患者中存在生物化学可检测到的前驱期的Pron病。 人类携带者。我们将分析出现症状前的人血浆和/或脑脊液样本，以寻找神经元标志物。 Pron种子的损害和存在，已知的与症状性Pron疾病相关的生物标志物，以 为了试验设计和分层的目的，了解有症状的携带者是否有证据表明 在症状出现之前，生化可检测到的病理性前驱期。

Human prion disease is a rare, exceptionally rapid, universally fatal neurodegenerative disease. Though currently untreatable, all prion disease follows a single well-characterized molecular mechanism by which the native prion protein (PrP), encoded by the prion protein gene (PRNP), misfolds into a pathogenic conformation. These so-called prions template the conformational corruption of healthy PrP molecules, propelling the spread of prions and prion-induced neurotoxicity across the brain. As the necessary substrate for prion conversion, native PrP has emerged as an attractive therapeutic target in prion disease. Decades of evidence indicate that reduction of native PrP is dose-dependently protective against prion disease. Full knockout confers total protection against disease, with animal and human evidence indicating that PrP reduction should be well tolerated. In light of these promising proofs of concept, we are collaborating with Ionis Pharmaceuticals to develop PrP-lowering antisense oligonucleotides (ASOs) that reduce PrP in the brain by targeting PrP RNA for degradation. Preliminary preclinical studies suggest that ASOs against prion protein potently extend survival of prion-infected animals, with prophylactic treatment conferring the greatest benefit. Our preliminary engagement with the FDA indicates that primary prevention trials in pre-symptomatic prion disease mutation carriers could be feasible, and that lowering PrP in cerebrospinal fluid (CSF) may be a viable surrogate endpoint for Accelerated Approval of a PrP-lowering therapeutic. Informed by FDA engagement, the following three aims will gather critical and time-sensitive data to enable this clinical path. 1) Assess short-term within-subject test-retest stability of CSF PrP in pre-symptomatic genetic prion disease mutation carriers and non-carrier controls. We will use a technically validated ELISA to determine short-term stability of PrP levels in repeat CSF samples donated by genetic prion disease carriers and controls over 2-4 month intervals. 2) Determine the correlation between brain and CSF PrP knockdown in rats, and between brain PrP knockdown and survival in mice. We will analyze ASO-treated rodent tissues to model the relationship between brain and CSF PrP levels, as well as the relationship between brain PrP knockdown and extension of survival. 3) Gather pathological biomarker data to assess presence of a biochemically detectable prodromal phase of prion disease in pre-symptomatic human carriers. We will analyze pre-symptomatic human plasma and/or CSF samples for markers of neuronal damage and presence of prion seeds, biomarkers known to be associated with symptomatic prion disease, to understand for purposes of trial design and stratification whether pre-symptomatic carriers show evidence of a biochemically detectable pathological prodromal phase prior to symptom onset.