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：
JORGE A BUSCIGLIO
金额：
$ 19.18万
依托单位：
UNIVERSITY OF COLORADO DENVER
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：
https://reporter.nih.gov/project-details/8990998
关键词：
Address Adult Adverse effects Affect Algorithms Animal Model Biological Biological Assay Brain Cell physiology Cells Chromosomes, Human, Pair 21 Clinical Clinical Trials Code Cognitive Cognitive deficits Complex Computational algorithm Computing Methodologies Cultured Cells Disease Dose Down Syndrome Drug Combinations Drug Design Drug usage Effectiveness Evaluation Evolution FDA approved Failure Feedback Future Gene Proteins Generations Genes Genetic Genetic Heterogeneity Goals Health Heterogeneity Human Human Chromosomes Incidence Individual Intellectual functioning disability Learning Life Expectancy Live Birth Measures Memory impairment Mitochondria Modeling Molecular Multiple Abnormalities Mus Neurons Orthologous Gene Outcome Pathway interactions Performance Pharmaceutical Preparations Pharmacotherapy Phenotype Population Preclinical Drug Evaluation Probability Production Proteins Reactive Oxygen Species Sampling Speed Synapses Synaptic plasticity System Testing Trisomy United States base behavior test brain abnormalities density drug testing fetal in vivo induced pluripotent stem cell innovation mouse Ts65Dn mouse model novel novel strategies overexpression postnatal preclinical evaluation preclinical trial response screening success trial 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）：唐氏综合症（DS）的发生率约为750个活产，是智力障碍（ID）的最常见遗传原因。尽管ID可能是温和的，但平均智商为〜40-50。在美国，目前，DS的人口估计约为350,000，并且随着预期寿命的增加而继续增加。因此，DS中认知缺陷的药物治疗将产生重大影响。当前，在DS基础中，在DS的DS基础上启动ID的临床试验的热情是在DS的一种鼠标模型TS65DN中启动临床试验。但是，三个因素可能会限制成功。首先，TS65DN仅对161个人类染色体中的88个（HSA21）蛋白质基因的三化。非创伤性HSA21直系同源物包括一些导致L/M缺陷和突触可塑性受损时。这些基因在DS中的表达会影响表型和可能的药物反应的分子基础。其次，人口中的遗传异质性也可能改变表型和药物反应。第三，一种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发性神经元和药物的测试组合。相对于对照组，来自DS胎儿大脑的神经元培养物显示突触密度降低，线粒体功能降低以及活性氧的水平升高。在AIM 1中，我们将通过分别用八种不同的药物治疗DS胎儿脑神经元培养物来拯救这些异常，每种药物已显示或预测在TS65DN或DS中有效。在AIM 2中，我们将使用一种新型的实验/计算方法，反馈系统控制（FSC），测试相同药物的组合来营救每种DS异常。当前，鉴定药物/剂量组合以治疗疾病是基于在临床环境中的高通量随机药物筛查或试验测试。相比之下，FSC提供了一个系统的搜索范式，该范式将实验测试与使用计算机算法相结合，以查找具有生物学有效的药物/剂量组合。至关重要的是，FSC表明，在广泛的药物/剂量中，生物学反应是平滑的。因此，搜索迅速收敛到最佳读数，仅需测试200-300个药物/剂量组合，而不是数十万。在AIM 3中，我们将将FSC扩展到Cascade FSC，以优化药物组合，以同时营救多个DS异常。我们提出的系统的重要优点是，i）它使用完整的人类三症HSA21神经元模型，ii）作为细胞系统，它允许快速筛选许多药物，ii）药物的组合更有可能有效地挽救多个途径异常，因此在多种途径中促进了这些较低的浓度，因此需要进行多个较低的毒品，并可能采用各种浓度，复杂的范围，复杂的范围，IV），IV，IV），IV，IIV，IV）。单独使用任何药物时需要；这将减少潜在的负相互作用和关闭目标影响； v）仅需要测试200-300个药物/剂量组合，而不是数十万。该应用的目的是确定药物组合的最佳剂量，这些药物共同挽救了DS神经元中存在多种异常。在未来的研究中，最终的融合药物组合将在皮质神经元培养物中进行测试，以挽救DS衍生的神经分化的诱导多能干细胞（IPSCS）中的其他异常，并且作为最终的临床前试验评估，在L/M DEFICITS的完整DS小鼠模型中。这项工作是一种新的方法，可以增加DS认知缺陷的临床试验的可能性。

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：
Aging cell
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