Combinational pharmacotherapies for neuronal abnormalities in Down syndrome
唐氏综合症神经元异常的联合药物疗法
基本信息
- 批准号:8990998
- 负责人:
- 金额:$ 19.18万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2015
- 资助国家:美国
- 起止时间:2015-01-01 至 2016-12-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAdultAdverse effectsAffectAlgorithmsAnimal ModelBiologicalBiological AssayBrainCell physiologyCellsChromosomes, Human, Pair 21ClinicalClinical TrialsCodeCognitiveCognitive deficitsComplexComputational algorithmComputing MethodologiesCultured CellsDiseaseDoseDown SyndromeDrug CombinationsDrug DesignDrug usageEffectivenessEvaluationEvolutionFDA approvedFailureFeedbackFutureGene ProteinsGenerationsGenesGeneticGenetic HeterogeneityGoalsHealthHeterogeneityHumanHuman ChromosomesIncidenceIndividualIntellectual functioning disabilityLearningLife ExpectancyLive BirthMeasuresMemory impairmentMitochondriaModelingMolecularMultiple AbnormalitiesMusNeuronsOrthologous GeneOutcomePathway interactionsPerformancePharmaceutical PreparationsPharmacotherapyPhenotypePopulationPreclinical Drug EvaluationProbabilityProductionProteinsReactive Oxygen SpeciesSamplingSpeedSynapsesSynaptic plasticitySystemTestingTrisomyUnited Statesbasebehavior testbrain abnormalitiesdensitydrug testingfetalin vivoinduced pluripotent stem cellinnovationmouse Ts65Dnmouse modelnovelnovel strategiesoverexpressionpostnatalpreclinical evaluationpreclinical trialresponsescreeningsuccesstrial design
项目摘要
DESCRIPTION (provided by applicant): With an incidence of approximately one in 750 live births, Down syndrome (DS) is the most common genetic cause of intellectual disability (ID). Although ID can be mild, the average IQ is ~40-50. In the United States, the population of people with DS is currently estimated at ~350,000 and continues to increase as the average life expectancy increases. Pharmacotherapies for cognitive deficits in DS would, therefore, have a significant impact. Currently, there is enthusiasm for initiating clinical trials for ID in DS base on rescue of learning/memory deficits in one mouse model of DS, the Ts65Dn. However, three factors may limit success. First, the Ts65Dn is trisomic for only 88 of 161 human chromosome 21 (HSA21) protein genes; non-trisomic HSA21 orthologs include some that cause L/M deficits and impaired synaptic plasticity when they are over expressed. Over expression of these genes in DS will affect the molecular basis of the phenotype and, possibly, drug responses. Second, genetic heterogeneity in the human population may also alter phenotype and drug responses. Third, a single drug may be insufficient to correct the many molecular and cellular perturbations that contribute to the complexity of human cognitive deficits. To address these three issues, we propose to use cultured human primary neurons and test combinations of drugs. Relative to controls, neuronal cultures from DS fetal brain show decreased synapse density, decreased mitochondrial function, and increased levels of reactive oxygen species. In Aim 1, we will test DS fetal brain neuronal cultures for rescue of these abnormalities by separately treating with eight different drugs, each of which has been shown or is predicted to be effective in the Ts65Dn or DS. In Aim 2, we will use a novel experimental/computational method, Feedback System Control (FSC), to test combinations of the same drugs for rescue of each DS abnormality. Currently, identifying drug/dose combinations to treat disease is based on high-throughput random drug screenings or trial-and-error testing in a clinical setting. In contrast, FSC provides a systematic search paradigm that combines experimental testing, in a cell system, with use of a computer algorithm to find biologically effective drug/dose combinations. Critically, FSC has shown that biological responses are smooth over a wide range of drugs/doses. Therefore the search rapidly converges to an optimal readout, requiring testing of only 200-300 drug/dose combinations, not hundreds of thousands. In Aim 3, we will extend FSC to Cascade FSC to optimize the drug combination for simultaneous rescue of multiple DS abnormalities. The important advantages of the system we propose are that i) it uses a complete human trisomy HSA21 neuronal model, ii) as a cell system, it allows rapid screening of many drugs, iii) a combination of drugs is more likely to be effective in rescuing multiple pathway abnormalities and therefore in rescuing circuits underlying multiple, complex cognitive failures, iv) the concentrations required for each drug in the combination likely will be lower tha those required when any drug is used alone; this will decrease potential negative interactions and off target effects; and v) only 200-300 drug/dose combinations need to be tested, not hundreds of thousands. The goal of this application is to identify the optimal doses of a combination of drugs that together rescue multiple abnormalities present in DS neurons. In future studies, the final converged drug combination will be tested in cortical neuronal cultures for rescue of additional abnormalities, in DS-derived neurally differentiated induced pluripotent stem cells (iPSCs), and, as a final preclinical trial evaluation, in a complete DS mouse model for rescue of L/M deficits. This effort is a novel approach to increase the probability that clinical trials for cognitive deficits in DS will be both safe and effective.
描述(由申请人提供):唐氏综合征(DS)的发病率约为750例活产婴儿中的1例,是智力残疾(ID)最常见的遗传原因。虽然ID可能是轻微的,但平均智商约为40-50。在美国,DS患者目前估计约为350,000人,并且随着平均预期寿命的增加而继续增加。因此,药物治疗DS认知缺陷将产生重大影响。目前,人们热衷于在DS的一种小鼠模型Ts 65 Dn中基于拯救学习/记忆缺陷来启动DS中ID的临床试验。然而,有三个因素可能会限制成功。首先,Ts 65 Dn对于161个人类21号染色体(HSA 21)蛋白基因中的仅88个是三体的;非三体HSA 21直系同源物包括当它们过度表达时引起L/M缺陷和受损的突触可塑性的一些。这些基因在DS中的过度表达将影响表型的分子基础,并可能影响药物反应。其次,人群中的遗传异质性也可能改变表型和药物反应。第三,单一药物可能不足以纠正导致人类认知缺陷复杂性的许多分子和细胞扰动。 为了解决这三个问题,我们建议使用培养的人类原代神经元和测试药物组合。相对于对照组,DS胎脑神经元培养物显示突触密度降低,线粒体功能降低,活性氧水平升高。在目标1中,我们将测试DS胎脑神经元培养物,通过分别用8种不同的药物治疗来挽救这些异常,每种药物都已被证明或预测在Ts 65 Dn或DS中有效。在目标2中,我们将使用一种新的实验/计算方法,反馈系统控制(FSC),以测试相同药物的组合,以挽救每种DS异常。目前,确定治疗疾病的药物/剂量组合是基于高通量随机药物筛选或临床环境中的试错测试。相比之下,FSC提供了一种系统的搜索范式,该范式将细胞系统中的实验测试与使用计算机算法相结合,以找到生物学上有效的药物/剂量组合。重要的是,FSC已经表明,生物反应在广泛的药物/剂量范围内是平稳的。因此,搜索快速收敛到最佳读数,仅需要测试200-300种药物/剂量组合,而不是数十万种。在目标3中,我们将FSC扩展到级联FSC,以优化药物组合,同时挽救多种DS异常。 我们提出的系统的重要优点是:i)它使用完整的人三体HSA 21神经元模型,ii)作为细胞系统,它允许快速筛选许多药物,iii)药物的组合更可能有效地挽救多个通路异常,因此更可能有效地挽救多个复杂认知障碍的潜在回路,iv)组合中每种药物所需的浓度可能低于单独使用任何药物时所需的浓度;这将减少潜在的负面相互作用和脱靶效应;和v)仅需要测试200-300种药物/剂量组合,而不是数十万种。 本申请的目的是确定药物组合的最佳剂量,这些药物组合一起拯救DS神经元中存在的多种异常。在未来的研究中,将在皮质神经元培养物中测试最终的融合药物组合以拯救其他异常,在DS衍生的神经分化的诱导多能干细胞(iPSC)中测试,并且作为最终的临床前试验评价,在完整的DS小鼠模型中测试以拯救L/M缺陷。这一努力是一种新的方法,以增加概率,认知缺陷的DS临床试验将是安全和有效的。
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Nrf2 stabilization prevents critical oxidative damage in Down syndrome cells.
- DOI:10.1111/acel.12812
- 发表时间:2018-10
- 期刊:
- 影响因子:7.8
- 作者:Zamponi E;Zamponi N;Coskun P;Quassollo G;Lorenzo A;Cannas SA;Pigino G;Chialvo DR;Gardiner K;Busciglio J;Helguera P
- 通讯作者:Helguera P
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JORGE A BUSCIGLIO其他文献
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