Developing RNA therapeutics for rare neurodevelopmental disorders
开发罕见神经发育障碍的 RNA 疗法
基本信息
- 批准号:10697291
- 负责人:
- 金额:$ 29.95万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-05-01 至 2025-04-30
- 项目状态:未结题
- 来源:
- 关键词:Academic Medical CentersAccelerationAffectAllelesAntisense OligonucleotidesBehaviorBehavioralBiological ModelsBrainCell ProliferationChemistryClinicalClinical Drug DevelopmentClinical TrialsCodeDNA MethylationDataDevelopmental Delay DisordersDevelopmental DisabilitiesDiseaseDominant-Negative MutationDoseDrug Delivery SystemsDrug ScreeningDrug TargetingExonsGene ExpressionGene ModifiedGene ProteinsGenesGenomic SegmentGoalsGrowthHeterozygoteHumanHuman Cell LineIn VitroIncidenceIndividualInjectionsIntellectual functioning disabilityKnowledgeLeadLifeLive BirthLoss of HeterozygosityMedicalMendelian disorderMessenger RNAMissionModalityModelingMolecularMusMutationNeurodevelopmental DisorderNonsense-Mediated DecayNuclear ReceptorsNucleic Acid Regulatory SequencesOpen Reading FramesOrganoidsPathologyPatientsPharmaceutical PreparationsPhasePoisonPopulationPrivatizationProductionProtein IsoformsProtein Structure InitiativeProteinsRNA SplicingRNA-targeting therapyRegulator GenesResolutionResourcesRiskSET DomainSeizuresSeriesSiteSmall Business Technology Transfer ResearchSotos syndromeSpecificitySpinal Muscular AtrophySupportive careSyndromeTechnologyTerminator CodonTertiary Protein StructureTherapeuticTherapeutic AgentsTherapeutic EffectTranscriptUp-RegulationValidationWalkingautism spectrum disorderclinical developmentde novo mutationdevelopmental diseasedisabling diseasedisease-causing mutationdravet syndromedrug discoveryeffective therapyefficacy evaluationefficacy validationexperimental studygene functiongene therapyhistone methyltransferasein vivoinduced pluripotent stem cellinnovationlead candidateloss of function mutationmeetingsmicrodeletionmind controlmouse modelnervous system disordernovelpre-Investigational New Drug meetingpre-clinicalpreclinical studyprogramsprotein functionreceptor bindingsuccesstherapeutic RNAtimelineuptake
项目摘要
PROJECT SUMMARY
Developing RNA therapeutics for rare neurodevelopmental disorders
Monogenic diseases caused by mutations in single genes are individually rare, but collectively common affecting
10% of the world population. Many of these diseases are disabling or even life threatening with no available
treatment. The underlying molecular mechanisms vary. Both loss of gene function and gain of toxic or dominant
negative effects can lead to pathology, and modification of gene expression could be disease modifying. DAYI
Therapeutics, Inc is a spin-out of Columbia University Medical Center that has the goal of advancing precisely
targeted RNA therapeutics for the treatment of rare monogenic diseases, especially neurological disorders
affecting the brain and behavior. Using a proprietary target discovery platform developed by our academic co-
founders, we have prioritized a list of target genes causing severe neurodevelopmental disorders with
tremendous unmet medical needs. These target genes are in general difficult to target with current approaches
but are druggable with our unique technology to identify endogenous, naturally occurring gene regulatory regions
that can be targeted by different therapeutic modalities including antisense oligonucleotides (ASOs). In this
proposal, we aim to develop the first therapeutic for a severe developmental and intellectual disability syndrome
by restoring gene expression and protein function using an ASO. The feasibility of our approach is supported
by compelling preliminary data. We propose to perform a systematic ASO drug screen to identify the most
effective ASOs as drug lead and then conduct a series of pre-clinical studies to validate their efficacy in correcting
the molecular, cellular and behavioral deficits caused by the mutation using patient-derived iPSCs, brain
organoids and mouse models. ASOs are an established therapeutic agent with the advantage of high target
specificity, clear mode of action, and accelerated timeline from drug discovery to clinical deployment. If
successful, this study will provide the critical first step to develop a novel ASO therapeutic to fulfill unmet medical
needs and potentially also serve as proof of principle for treatment of neurodevelopmental disorders caused by
mutations in a wide range of genes.
项目概要
开发罕见神经发育障碍的 RNA 疗法
由单个基因突变引起的单基因疾病个别罕见,但总体上常见
世界人口的10%。其中许多疾病会导致残疾甚至危及生命,而没有可用的治疗方法。
治疗。潜在的分子机制各不相同。基因功能的丧失和有毒或显性基因功能的增加
负面影响可能导致病理,而基因表达的改变可能会改变疾病。大易
Therapeutics, Inc 是哥伦比亚大学医学中心的衍生公司,其目标是精准推进
用于治疗罕见单基因疾病,特别是神经系统疾病的靶向 RNA 疗法
影响大脑和行为。使用我们的学术合作伙伴开发的专有目标发现平台
创始人,我们优先考虑了一系列导致严重神经发育障碍的靶基因
巨大的未满足的医疗需求。这些靶基因通常很难用目前的方法来靶向
但可以通过我们独特的技术来识别内源性、自然发生的基因调控区域
可以通过不同的治疗方式(包括反义寡核苷酸(ASO))来靶向。在这个
提案中,我们的目标是开发第一种治疗严重发育和智力障碍综合症的疗法
通过使用 ASO 恢复基因表达和蛋白质功能。我们的方法的可行性得到了支持
通过令人信服的初步数据。我们建议进行系统的 ASO 药物筛选,以识别最
有效的ASO作为药物先导物,然后进行一系列的临床前研究来验证其纠正的功效
使用患者来源的 iPSC、脑部突变引起的分子、细胞和行为缺陷
类器官和小鼠模型。 ASO 是一种成熟的治疗药物,具有高靶点优势
特异性、明确的作用方式以及从药物发现到临床部署的加速时间表。如果
如果成功的话,这项研究将为开发一种新型 ASO 疗法来满足未满足的医疗需求迈出关键的第一步。
的需求,也可能作为治疗由以下原因引起的神经发育障碍的原理证明:
多种基因的突变。
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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Francesco Lotti其他文献
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METTL3-mediated regulation of motor neuron function
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- 批准号:
10781077 - 财政年份:2023
- 资助金额:
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9387954 - 财政年份:2017
- 资助金额:
$ 29.95万 - 项目类别:
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