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: 10599901
• 负责人: Robert H. Brown
• 金额: $ 63.51万
• 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 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10599901
• 关键词: Adult; Affect; Age; Alleles; Alzheimer' s Disease; Amyotrophic Lateral Sclerosis; Animal Model; Antisense Oligonucleotides; Biological Assay; C9ORF72; Central Nervous System; 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; 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; Sulfur; Technology; Testing; Therapeutic; Therapeutic Agents; Therapeutic Index; Toxic effect; Vertebral column; Wild Type Mouse; age related; alpha synuclein; analog; burden of illness; clinical development; clinically relevant; disease phenotype; drug candidate; effective therapy; efficacy evaluation; 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; profilin 1; sugar; superoxide dismutase 1; synuclein; technology platform; transcriptome; transmission process; 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.

项目摘要 神经退行性疾病是毁灭性的与年龄相关的疾病，代表了一种巨大的疾病 全球负担。随着人口年龄的增长，对有效疗法的需求越来越紧迫。大多数家庭 成人发作的神经退行性疾病是由主要传播基因缺陷引起的（例如C9orf72 和ALS中的SOD1，亨廷顿的HTT，帕金森氏症中的α-核蛋白。那是一种主要的方法 这种疾病的治疗是抑制违法基因的表达。反义寡核苷酸 （ASOS）是主要结构神经退行性疾病的有前途的治疗类别。一个ASO 已获得批准治疗脊柱肌肉萎缩，另外五个正在接受亨廷顿的临床试验， 阿尔茨海默氏病，ALS和额颞痴呆（FTD）。 然而，ASO治疗领域中有两个关键的未满足需求，需要紧急和 集中投资。首先是通常在大多数寡核苷酸药物 当施用到中枢神经系统中时会引起毒性。我们已经确定了减轻这种情况的方法 通过改变主链修饰模式的毒性。但是，当前的方法增加了 对核酸酶消化的敏感性，这将减少效果持续时间。在这个建议中，我们将开发小说 混合背骨寡核苷酸，将效力进一步增加并随长时间降低毒性 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，成功的热方法将 需要区分突变体和野生型（健康）等位基因，使突变拷贝沉默 使野生型副本完好无损。我们将同时使用创新的测定和新颖的化学修饰 提高ASO区分这些等位基因的能力。 应用这些见解，我们将推动两个ALS和ALS-FTD基因的候选药物（C9orf72和 在动物模型中，我们已经建立了这些疾病的广泛测试。我们将检查 我们的高级ASO在分子水平和水平上的安全性，有效性和效果持续时间 疾病表型的变化。 在此提案中，我们的实验室将创新化学与神经病学和深层专家相结合 与疾病相关的小鼠模型。我们旨在开发广泛适用的平台技术， 相对于临床发育中当前的ASO的热指数的改善。而且，我们会的 确定用于C9orf72-和Profilin1依赖性ALS-FTD的新型等位基因选择性候选药物候选物。

项目成果

Variant-selective stereopure oligonucleotides protect against pathologies associated with C9orf72-repeat expansion in preclinical models.

• DOI: 10.1038/s41467-021-21112-8
• 发表时间: 2021-02-08
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Liu Y;Dodart JC;Tran H;Berkovitch S;Braun M;Byrne M;Durbin AF;Hu XS;Iwamoto N;Jang HG;Kandasamy P;Liu F;Longo K;Ruschel J;Shelke J;Yang H;Yin Y;Donner A;Zhong Z;Vargeese C;Brown RH Jr
• 通讯作者: Brown RH Jr

Quantification of Antisense Oligonucleotides by Splint Ligation and Quantitative Polymerase Chain Reaction.

• DOI: 10.1089/nat.2021.0040
• 发表时间: 2022-03
• 期刊: Nucleic acid therapeutics
• 影响因子: 4
• 作者: Shin M;Meda Krishnamurthy P;Devi G;Watts JK
• 通讯作者: Watts JK

G-rich motifs within phosphorothioate-based antisense oligonucleotides (ASOs) drive activation of FXN expression through indirect effects.

• DOI: 10.1093/nar/gkac1108
• 发表时间: 2022-12-09
• 期刊: NUCLEIC ACIDS RESEARCH
• 影响因子: 14.9
• 作者: Wang, Feng;Calvo-Roitberg, Ezequiel;Rembetsy-Brown, Julia M.;Fang, Minggang;Sousa, Jacquelyn;Kartje, Zachary J.;Krishnamurthy, Pranathi Meda;Lee, Jonathan;Green, Michael R.;Pai, Athma A.;Watts, Jonathan K.
• 通讯作者: Watts, Jonathan K.