Reading Frame Correction for the Treatment of Batten Disease
阅读框架校正治疗 Batten 病
基本信息
- 批准号:10597534
- 负责人:
- 金额:$ 58.13万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-05-01 至 2023-05-15
- 项目状态:已结题
- 来源:
- 关键词:AccelerationAddressAffectAgeAge YearsAlternative SplicingAmino Acid SequenceAnimal ModelAntisense OligonucleotidesBase SequenceBehaviorBiological AssayBiological MarkersBiologyBlindnessBrainC-terminalCLN3 geneCell modelCellsCessation of lifeChildChildhoodClinical TrialsCognitiveDataDementiaDiseaseDisease ProgressionDisease modelDoseEnsureExonsEyeFamily suidaeFunctional disorderGenesGoalsHealthHumanHuman Cell LineIn VitroInvestigational DrugsLabelLengthLifeLife ExpectancyLysosomal Storage DiseasesMediatingMessenger RNAMotorMusMutateMutationNerve DegenerationNeurologicNeuronsOpen Reading FramesPathologyPatientsPharmacodynamicsProductionProtein IsoformsProtein TruncationProteinsRNA SplicingReading FramesRecoveryResearchRetinaScientistSeizuresSpielmeyer-Vogt DiseaseSymptomsTerminator CodonTestingTherapeuticTherapeutic EffectTissuesTranslatingTransmembrane DomainVisionautosomecognitive disabilitydisease phenotypeearly childhoodeffective therapyhuman modelimprovedin vitro activityin vivoin vivo monitoringinnovationmRNA Precursormouse modelmutantneuropathologynew therapeutic targetnovelnovel strategiesporcine modelpreclinical developmentpreclinical efficacyprematureprotein functionstandard of caresuccesstherapeutic developmenttherapeutic targettooltraffickingtreatment strategy
项目摘要
CLN3 Batten disease is a fatal lysosomal storage disorder (LSD) resulting from autosomal recessive mutations
in CLN3. The disease progresses from vision loss in early childhood to seizures, motor decline, cognitive
disability and dementia, with a typical life expectancy of 15-30 years of age. There is no cure for CLN3 Batten
and the only treatments available address some disease symptoms, but do not delay disease progression. The
discovery of an effective treatment for CLN3 Batten has been hindered by a lack of understanding of the
protein's function and the underlying mechanisms leading to neurodegeneration. The goal of this proposal is to
test a therapeutic approach for CLN3 Batten that employs antisense oligonucleotides (ASOs) and in so doing,
elucidate mechanisms of neurodegeneration in this disease that will inform research and discovery of effective
treatments for Batten diseases and other LSDs. Most cases of CLN3 Batten are caused by deletion of exons 7
and 8 (CLN3Δ78), which results in an open reading frame shift and a premature termination codon. We
hypothesize that using ASOs to redirect pre-mRNA splicing and correct the reading frame of CLN3Δ78 mRNA
will partially restore protein function and have a therapeutic effect in CLN3 Batten disease. Our preliminary
findings support our hypothesis, demonstrating that restoring the CLN3Δ78 reading frame alleviates dysfunction
associated with disease in both cell and animal models. We will test our hypothesis in the proposed project
with the aims to 1) compare the function of the wild type and novel CLN3 isoforms, 2) develop an approach
using ASOs to increase CLN3Δex78 isoforms, 3) assess ASO treatments for CLN3 Batten disease using human
cell lines as well as mouse and 4) porcine models of CLN3 Batten disease. Collectively, this study will allow us
to better understand the function of the CLN3 protein and the utility of ASOs in treating CLN3 Batten disease.
CLN 3 Batten病是一种由常染色体隐性突变引起的致命性溶酶体储积症(LSD)
在CLN 3中。该疾病从儿童早期的视力丧失发展为癫痫发作、运动能力下降、认知障碍、认知
残疾和痴呆,典型的预期寿命为15-30岁。CLN 3 Batten无法治愈
仅有的治疗方法可以解决一些疾病症状,但不能延缓疾病进展。的
对CLN 3 Batten的有效治疗的发现受到缺乏对CLN 3治疗的理解的阻碍。
蛋白质的功能和导致神经变性的潜在机制。本提案的目的是
测试采用反义寡核苷酸(ASO)的CLN 3 Batten的治疗方法,
阐明这种疾病的神经变性机制,将为研究和发现有效的
治疗巴顿病和其他迷幻药大多数CLN 3 Batten病例是由外显子7缺失引起的
和8(CLN 3 Δ78),这导致开放阅读移码和提前终止密码子。我们
假设使用ASO重定向CLN 3 Δ78 mRNA的前体剪接并校正其阅读框
将部分恢复蛋白质功能,并对CLN 3 Batten病有治疗作用。我们的初步
研究结果支持我们的假设,表明恢复CLN 3 Δ78阅读框架会导致功能障碍
与细胞和动物模型中的疾病相关。我们将在拟议的项目中检验我们的假设
目的是1)比较野生型和新型CLN 3同种型的功能,2)开发一种方法,
使用ASO增加CLN 3 Δ ex 78同种型,3)使用人类评估CLN 3巴滕病的阿索治疗
细胞系以及CLN 3 Batten病的小鼠和4)猪模型。总的来说,这项研究将使我们
更好地了解CLN 3蛋白的功能和ASO在治疗CLN 3 Batten病中的效用。
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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Michelle L Hastings其他文献
Michelle L Hastings的其他文献
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{{ truncateString('Michelle L Hastings', 18)}}的其他基金
Reading Frame Correction for the Treatment of Batten Disease
阅读框架校正治疗 Batten 病
- 批准号:
11003569 - 财政年份:2020
- 资助金额:
$ 58.13万 - 项目类别:
Reading Frame Correction for the Treatment of Batten Disease
阅读框架校正治疗 Batten 病
- 批准号:
9917402 - 财政年份:2020
- 资助金额:
$ 58.13万 - 项目类别:
Reading Frame Correction for the Treatment of Batten Disease
阅读框架校正治疗 Batten 病
- 批准号:
10383400 - 财政年份:2020
- 资助金额:
$ 58.13万 - 项目类别:
Correction of Hearing and Vestibular Defects in a Mouse Model for Deafness
小鼠耳聋模型中听力和前庭缺陷的矫正
- 批准号:
8496335 - 财政年份:2013
- 资助金额:
$ 58.13万 - 项目类别:
Correction of Hearing and Vestibular Defects in a Mouse Model for Deafness
小鼠耳聋模型中听力和前庭缺陷的矫正
- 批准号:
8611805 - 财政年份:2013
- 资助金额:
$ 58.13万 - 项目类别:
Targeting SMN2 Alternative Splicing for the Treatment of Spinal Muscular Atrophy
靶向 SMN2 选择性剪接治疗脊髓性肌萎缩症
- 批准号:
8642676 - 财政年份:2010
- 资助金额:
$ 58.13万 - 项目类别:
Targeting SMN2 Alternative Splicing for the Treatment of Spinal Muscular Atrophy
靶向 SMN2 选择性剪接治疗脊髓性肌萎缩症
- 批准号:
8236969 - 财政年份:2010
- 资助金额:
$ 58.13万 - 项目类别:
Targeting SMN2 Alternative Splicing for the Treatment of Spinal Muscular Atrophy
靶向 SMN2 选择性剪接治疗脊髓性肌萎缩症
- 批准号:
8037088 - 财政年份:2010
- 资助金额:
$ 58.13万 - 项目类别:
Targeting SMN2 Alternative Splicing for the Treatment of Spinal Muscular Atrophy
靶向 SMN2 选择性剪接治疗脊髓性肌萎缩症
- 批准号:
7866381 - 财政年份:2010
- 资助金额:
$ 58.13万 - 项目类别:
Targeting SMN2 Alternative Splicing for the Treatment of Spinal Muscular Atrophy
靶向 SMN2 选择性剪接治疗脊髓性肌萎缩症
- 批准号:
8432873 - 财政年份:2010
- 资助金额:
$ 58.13万 - 项目类别:
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