Antisense Oligonucleotides for treating Spinocerebellar Ataxia Type 2
用于治疗 2 型脊髓小脑共济失调的反义寡核苷酸
基本信息
- 批准号:9912849
- 负责人:
- 金额:$ 74.37万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-02-15 至 2022-01-31
- 项目状态:已结题
- 来源:
- 关键词:AcuteAffectAllelesAmyotrophic Lateral SclerosisAnimal ModelAntisense Oligonucleotide TherapyAntisense OligonucleotidesBacterial Artificial ChromosomesBrainCause of DeathCellsCellular MorphologyCerebellumCessation of lifeChemistryClinicalClinical TrialsDataDiseaseDoseDown-RegulationEconomic BurdenEconomicsFDA approvedFeasibility StudiesGenesHalf-LifeHealthHumanHuntington DiseaseIn VitroIndividualInjectionsInterventionKnock-outLeadMacaca fascicularisMalignant NeoplasmsModificationMolecularMorphologyMotorMotor NeuronsMusMutateMyotonic dystrophy type 1Nerve DegenerationNervous System Heredodegenerative DisordersNeurodegenerative DisordersNeuronsPathway interactionsPatientsPharmaceutical PreparationsPharmacologic SubstancePhenotypePhysiologicalPhysiologyPreclinical TestingProgressive DiseaseProteinsPurkinje CellsRattusResearchRodentSCA2 proteinSafetyScreening ResultSeverity of illnessSiteSliceSpinal CordSpinal Muscular AtrophySpinal cord grey matter structureStainsSymptomsTestingTherapeuticTimeTissuesToxic effectToxicity TestsToxicologyTransgenic MiceType 2 Spinocerebellar AtaxiaWild Type MouseWorkbasedesigndosageeffective therapyfirst-in-humangain of functionhigh throughput screeninghuman diseaseimprovedin vivolead candidatemRNA Precursormeetingsmembermolecular phenotypemouse modelmutantneurophysiologynovel therapeuticspolyglutaminepotency testingprematureprotein TDP-43protein aggregationprotein biomarkersprotein expressionresponsesafety testingscreeningsuccesstreatment grouptreatment responseuptake
项目摘要
Neurodegenerative diseases represent an ever-increasing societal and economic burden with WHO estimates indicating that they will replace cancer as the 2nd leading cause of death by 2040. In neurodegenerative disease research, a wealth of pathways has been uncovered, but their direct and primary relevance to the respective human disease has been difficult to prove and targeting of pathways has remained difficult. The proposed work will identify a treatment for spinocerebellar ataxia type 2 (SCA2), a hereditary neurodegenerative disease affecting cerebellar Purkinje cells (PCs) and other neurons in the cerebellum, the subcortical grey matter and spinal cord. The cause of SCA2 is a gain-of-function CAG expansion in the ATXN2 gene resulting in an expanded polyglutamine (polyQ) domain in ataxin-2. Our objective is identification of highly-potent antisense oligonucleotides (ASOs) that lower ATXN2 expression. Our rationale is based on observations in model organisms and humans indicating that higher dosages of the mutant allele/protein worsen disease severity and that down-regulation of mutant polyQ protein expression in rodents reverses clinical manifestations even after mice have become symptomatic. Additionally, complete knock-out of ATXN2 in mice does not cause neurodegeneration or premature death. Merit for this study is supported by positive results in ongoing clinical trials to test ASOs for treating amyotrophic lateral sclerosis (ALS) and myotonic dystrophy type 1 (DM1), as well as the success of SPINRAZA™ (Nusinersen) for spinal muscular atrophy (SMA), the first ever FDA approved ASO drug for a neurodegenerative disorder. The feasibility of this study is based on our positive proof-of-concept data demonstrating that our lead ATXN2 ASO delays progressive rodent SCA2 motor, molecular, and neurophysiological phenotypes after symptom onset. Five specific aims are proposed: 1) an intensive in vitro screen of ASOs targeting throughout the ATXN2 pre-mRNA including cultured SCA2 patient cells, 2) in vivo screens to identify leads lowering cerebellar ATXN2 in mice, 3) safety toxicity testing in rodents and other species, 4) testing the ASO leads for delaying established SCA2 mouse motor, molecular, and neurophysiological phenotypes, and 5) GMP manufacturing of the single most potent ASO candidate and pre-investigative new drug (IND) meetings with members of the FDA. The proposed work will break new ground for treatment of neurodegenerative diseases by demonstrating feasibility of targeting dominant-acting mutated polyQ genes with antisense oligonucleotides.
神经退行性疾病代表着不断增加的社会和经济负担,世界卫生组织估计,到 2040 年,神经退行性疾病将取代癌症成为第二大死因。在神经退行性疾病研究中,已经发现了大量的通路,但它们与相应人类疾病的直接和主要相关性很难证明,而且通路的靶向仍然很困难。拟议的工作将确定 2 型脊髓小脑共济失调 (SCA2) 的治疗方法,这是一种影响小脑浦肯野细胞 (PC) 和小脑、皮质下灰质和脊髓中其他神经元的遗传性神经退行性疾病。 SCA2 的原因是 ATXN2 基因中的功能获得性 CAG 扩展,导致 ataxin-2 中的聚谷氨酰胺 (polyQ) 结构域扩展。我们的目标是鉴定可降低 ATXN2 表达的高效反义寡核苷酸 (ASO)。我们的基本原理是基于对模型生物和人类的观察,表明较高剂量的突变等位基因/蛋白质会恶化疾病的严重程度,并且即使在小鼠出现症状后,啮齿类动物中突变polyQ蛋白表达的下调也会逆转临床表现。此外,完全敲除小鼠中的 ATXN2 不会导致神经变性或过早死亡。这项研究的优点得到了正在进行的测试 ASO 治疗肌萎缩侧索硬化症 (ALS) 和 1 型强直性肌营养不良 (DM1) 临床试验的积极结果的支持,以及 SPINRAZA™ (Nusinersen) 治疗脊髓性肌萎缩症 (SMA) 的成功,这是 FDA 批准的第一个用于治疗神经退行性疾病的 ASO 药物。这项研究的可行性基于我们积极的概念验证数据,证明我们的主要 ATXN2 ASO 可以延迟症状出现后啮齿类动物 SCA2 运动、分子和神经生理学表型的进展。提出了五个具体目标:1)针对整个 ATXN2 前 mRNA(包括培养的 SCA2 患者细胞)进行 ASO 的强化体外筛选,2)体内筛选以确定降低小鼠小脑 ATXN2 的引线,3)在啮齿动物和其他物种中进行安全毒性测试,4)测试 ASO 引线以延迟已建立的 SCA2 小鼠运动、分子和神经生理学 表型,以及 5) 单一最有效的 ASO 候选药物的 GMP 生产以及与 FDA 成员举行的预研究新药 (IND) 会议。拟议的工作将通过证明用反义寡核苷酸靶向显性作用突变的polyQ基因的可行性,为神经退行性疾病的治疗开辟新天地。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Stefan M. PULST其他文献
Stefan M. PULST的其他文献
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{{ truncateString('Stefan M. PULST', 18)}}的其他基金
Ataxin-2 complex proteins in neurodegeneration.
神经变性中的 Ataxin-2 复合蛋白。
- 批准号:
10450573 - 财政年份:2022
- 资助金额:
$ 74.37万 - 项目类别:
Targeting STAU1 for TDP-43 proteinopathies
靶向 STAU1 治疗 TDP-43 蛋白病
- 批准号:
10512615 - 财政年份:2022
- 资助金额:
$ 74.37万 - 项目类别:
Ataxin-2 complex proteins in neurodegeneration.
神经变性中的 Ataxin-2 复合蛋白。
- 批准号:
10612474 - 财政年份:2022
- 资助金额:
$ 74.37万 - 项目类别:
Characterization of ATXN2 as a target for ALS in SCA2 motor neurons
ATXN2 作为 SCA2 运动神经元 ALS 靶标的表征
- 批准号:
9601486 - 财政年份:2018
- 资助金额:
$ 74.37万 - 项目类别:
Comp B-Western Intermountain Regional NMD STARnet
比较 B-西部山间区域 NMD STARnet
- 批准号:
8915498 - 财政年份:2014
- 资助金额:
$ 74.37万 - 项目类别:
Comp B-Western Intermountain Regional NMD STARnet
比较 B-西部山间区域 NMD STARnet
- 批准号:
8821956 - 财政年份:2014
- 资助金额:
$ 74.37万 - 项目类别:
Identification of mutation causing Purkinje cell degeneration in the shaker rat
引起摇床大鼠浦肯野细胞变性的突变的鉴定
- 批准号:
8512375 - 财政年份:2013
- 资助金额:
$ 74.37万 - 项目类别:
Antisense oligonucleotides for the treatment of spinocerebellar ataxia type 2
用于治疗 2 型脊髓小脑共济失调的反义寡核苷酸
- 批准号:
8683274 - 财政年份:2013
- 资助金额:
$ 74.37万 - 项目类别:
Antisense oligonucleotides for the treatment of spinocerebellar ataxia type 2
用于治疗 2 型脊髓小脑共济失调的反义寡核苷酸
- 批准号:
8584105 - 财政年份:2013
- 资助金额:
$ 74.37万 - 项目类别:
Drug Discovery for Spinocerebellar Ataxia Type 2 (SCA2)
治疗 2 型脊髓小脑共济失调 (SCA2) 的药物发现
- 批准号:
8047349 - 财政年份:2010
- 资助金额:
$ 74.37万 - 项目类别:
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