Next-generation antisense therapeutics for ALS and frontotemporal dementia

针对 ALS 和额颞叶痴呆的下一代反义疗法

• 批准号: 9765950
• 负责人: Robert H. Brown
• 金额: $ 66.04万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-15 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9765950
• 关键词: Adult; Affect; Age; Alleles; Alzheimer' s Disease; Amyotrophic Lateral Sclerosis; Animal Model; Antisense Oligonucleotides; Biological Assay; C9ORF72; Chemicals; Chemistry; Clinical; Clinical Trials; Defect; Dementia; Digestion; Discrimination; Disease; Disease model; Dose; Exonuclease; Exposure to; Fibroblasts; Frontotemporal Dementia; Gene Silencing; Genes; Genetic; Genetic Diseases; Goals; Huntington Disease; Huntington gene; Inherited; Investments; Laboratories; Lead; Measures; Methods; Mixed-Backbone Oligonucleotide; Modeling; Modification; Molecular; Morbidity - disease rate; Mus; Neuraxis; Neurodegenerative Disorders; Neurology; Oligonucleotides; Oxygen; Parkinson Disease; Patients; Pattern; Peptide Nucleic Acids; Pharmaceutical Preparations; Phenotype; Population; Predisposition; Property; Research; Safety; Shapes; Specificity; Spinal Muscular Atrophy; Sugar Phosphates; Sulfur; Technology; Testing; Therapeutic; Therapeutic Agents; Therapeutic Index; Toxic effect; Vertebral column; Wild Type Mouse; age related; alpha synuclein; analog; base; burden of illness; clinical development; clinically relevant; combat; disease phenotype; drug candidate; effective therapy; efficacy study; frontotemporal lobar dementia-amyotrophic lateral sclerosis; improved; in vivo; innovation; inorganic phosphate; insight; mortality; mouse model; mutant; nervous system disorder; next generation; novel; nuclease; nucleobase; phosphorothioate; profilin 1; sugar; superoxide dismutase 1; synuclein; transcriptome; uptake

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.

项目概要 神经退行性疾病是一种破坏性的与年龄相关的疾病，是一种巨大的疾病 随着大多数家庭人口老龄化，对有效治疗的需求日益迫切。 成人发病的神经退行性疾病是由显性遗传基因缺陷引起的（例如 C9ORF72 和 ALS 中的 SOD1、亨廷顿舞蹈症中的 HTT、帕金森舞蹈症中的 α-突触核蛋白）。 此类疾病的治疗方法是抑制反义寡核苷酸的表达。 （ASO）是一类有前途的显性遗传性神经退行性疾病治疗方法。 已被批准用于治疗脊髓性肌萎缩症，另外五个药物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，ASO 治疗领域有两个关键的未满足需求，需要紧急和 首先是大多数寡核苷酸药物中经常使用的硫代磷酸酯主链。 当注射到中枢神经系统时会产生毒性，我们已经找到了减轻这种情况的方法。 然而，目前的方法增加了主链修饰模式的毒性。 对核酸酶消化的敏感性，这将减少效果的持续时间在本提案中，我们将开发新的。 混合主链寡核苷酸结合了长链的进一步增强效力和降低毒性 效果持续时间。 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 需要区分突变体和野生型（健康）等位基因，沉默突变体副本，同时 我们将使用创新的检测方法和新颖的化学修饰来保持野生型副本的完整性。 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（C9orf72 和 Profilin1) 在我们建立的这些疾病的动物模型中进行广泛的测试。 我们先进的 ASO 在分子水平和药物水平上的安全性、有效性和持续时间 疾病表型的改变。 在这项提案中，我们的实验室将把创新化学与神经学和神经学领域的深厚专业知识结合起来。 我们的目标是开发具有广泛适用性的平台技术。 此外，我们将相对于目前临床开发中的 ASO 改善治疗指数。 确定 C9orf72 和 profilin1 依赖性 ALS-FTD 的新型等位基因选择性候选药物。