Next-generation antisense therapeutics for ALS and frontotemporal dementia

项目摘要 神经退行性疾病是破坏性的年龄相关性疾病，代表了一个巨大的疾病 全球负担。随着人口老龄化，对有效治疗的需求越来越迫切。最具家族性 成人发病的神经退行性疾病是由显性传递基因缺陷（例如C9 ORF 72）引起的 ALS中的SOD 1、亨廷顿氏病中的HTT、帕金森氏病中的α-突触核蛋白）。因此，一种实现初级 治疗这些疾病的方法是抑制致病基因的表达。反义寡核苷酸 （ASO）是用于显性遗传性神经退行性疾病的一类有前景的治疗剂。的一个阿索 已经被批准用于治疗脊髓性肌萎缩症，另外五种正在进行亨廷顿舞蹈症的临床试验， 阿尔茨海默病、ALS和额颞叶痴呆（FTD）。 然而，在阿索治疗领域中存在两个关键的未满足的需求，这两个需求需要迫切和有效的治疗。 重点投资。第一个是大多数寡核苷酸药物中使用的硫代磷酸酯骨架通常 当进入中枢神经系统时会引起毒性。我们已经找到了缓解这种情况的方法 通过主链修饰模式的变化来降低毒性。然而，目前的做法增加了 对核酸酶消化的敏感性，这将减少作用的持续时间。在这个项目中，我们将开发新的 联合收割机的混合骨架寡核苷酸进一步增加效力并降低毒性， 效果的持续时间。 第二个未满足的关键需求是，对于许多疾病基因，成功的治疗方法将 需要区分突变和野生型（健康）等位基因，沉默突变拷贝， 留下野生型拷贝完整。我们将使用创新的检测方法和新型化学修饰， 提高ASO区分这些等位基因的能力。 应用这些见解，我们将推进两种ALS和ALS-FTD基因（C9 orf 72和C9 orf 73）的候选药物。 profilin 1）在我们已经建立的这些疾病的动物模型中进行广泛的测试。我们会研究 我们的先进ASO在分子水平和药物水平的安全性、有效性和作用持续时间 疾病表型的改变。 在这项提案中，我们的实验室将联合收割机创新化学与神经病学的深厚专业知识相结合， 疾病相关小鼠模型。我们的目标是开发广泛适用的平台技术， 治疗指数相对于目前临床开发中的ASO有所改善。而且还要 鉴定C9 orf 72和profilin 1依赖性ALS-FTD新等位基因选择性候选药物。

Project Summary Neurodegenerative diseases are devastating age-related disorders that represent a tremendous disease burden worldwide. The need for effective therapies is increasingly urgent as the population ages. Most familial adult-onset neurodegenerative disorders are caused by dominantly-transmitted gene defects (e.g. C9ORF72 and SOD1 in ALS, HTT in Huntington's, α-synuclein in Parkinson's). Thus, one approach toward primary therapy for such disorders is to suppress expression of the offending genes. Antisense oligonucleotides (ASOs) are a promising class of therapeutics for dominantly-inherited neurodegenerative disorders. One ASO has been approved to treat spinal muscular atrophy, and five others are in clinical trials for Huntington's, Alzheimer's disease, ALS, and frontotemporal dementia (FTD). Nevertheless, there are two key unmet needs in the field of ASO therapeutics which require urgent and focused investment. The first is that the phosphorothioate backbone used in most oligonucleotide drugs often causes toxicity when administered into the central nervous system. We have identified ways to mitigate this toxicity through changes in the backbone modification pattern. However, the current approaches increase susceptibility to nuclease digestion, which will reduce duration of effect. In this proposal we will develop novel mixed-backbone oligonucleotides that combine further increases in potency and decreases in toxicity with long duration of effect. The second key unmet need is that for many disease genes, successful therapeutic approaches would need to discriminate between the mutant and wild-type (healthy) alleles, silencing the mutant copy while leaving the wild-type copy intact. We will use both innovative assays and novel chemical modifications to improve the ability of ASOs to discriminate between these alleles. Applying these insights, we will advance drug candidates for two ALS and ALS-FTD genes (C9orf72 and profilin1) into extensive testing in animal models we have established of these diseases. We will examine the safety, efficacy and duration of effect of our advanced ASOs both at the molecular level and at the level of change in disease phenotype. In this proposal, our laboratories will combine innovative chemistry with deep expertise in neurology and disease-relevant mouse models. We aim to develop broadly applicable platform technology with a substantial improvement in therapeutic index relative to the ASOs currently in clinical development. Moreover, we will identify novel allele-selective candidate drug candidates for C9orf72- and profilin1-dependent ALS-FTD.