Next-generation antisense therapeutics for ALS and frontotemporal dementia

项目摘要 神经退行性疾病是一种破坏性的年龄相关疾病，是一种巨大的疾病。 全球范围内的负担。随着人口老龄化，对有效疗法的需求日益迫切。最具亲和力的 成人起病的神经退行性疾病是由显性传递的基因缺陷(例如C9ORF72)引起的 肌萎缩侧索硬化症、亨廷顿病、帕金森病的α-突触核蛋白)。因此，一种主要的方法是 这种疾病的治疗方法是抑制致病基因的表达。反义寡核苷酸 ASO是一类很有前途的治疗显性遗传性神经退行性疾病的药物。一个ASO 已被批准用于治疗脊髓性肌萎缩症，其他五人正在进行亨廷顿氏症的临床试验， 阿尔茨海默病、肌萎缩侧索硬化症和额颞叶痴呆(FTD)。 然而，在ASO治疗领域有两个关键的未得到满足的需求，需要紧急和 集中投资。第一种是大多数寡核苷酸药物中使用的硫代磷酸骨架通常 在中枢神经系统给药时会引起毒性。我们已经找到了缓解这种情况的方法 通过改变骨架修饰模式而产生毒性。然而，目前的方法增加了 对核酸酶消化敏感，这会缩短作用时间。在这项提案中，我们将开发新的 结合进一步增强效力和降低毒性的混合骨架寡核苷酸与Long 有效期。 第二个未得到满足的关键需求是，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，使突变副本沉默，同时 保持野生型复制品完好无损。我们将使用创新的分析方法和新的化学修饰来 提高ASOS区分这些等位基因的能力。 应用这些见解，我们将提出两个ALS和ALS-FTD基因(C9orf72和 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。我们将研究 我们先进的ASOS在分子水平和血管内皮细胞水平的安全性、有效性和持续时间 疾病表型的变化。 在这项提议中，我们的实验室将把创新的化学与深厚的神经学和 疾病相关的小鼠模型。我们的目标是开发广泛适用的平台技术，具有实质性的 相对于目前正在临床开发的ASOS，治疗指数有所改善。此外，我们还将 确定C9orf72和Profilin1依赖的ALS-FTD的新的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.