Lowe Syndrome: Therapeutic Strategy by Drug Repositioning

Lowe 综合征：药物重新定位的治疗策略

• 批准号: 9240037
• 负责人: Ruben Claudio Aguilar
• 金额: $ 22.66万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9240037
• 关键词: Address; Affect; Agreement; Animal Model; Binding; Biochemical; Biological Assay; Birth; Cataract; Categories; Cause of Death; Cells; Cessation of life; Characteristics; Child; Cilia; Clathrin; Defect; Dextrans; Disease; Drug Combinations; Exhibits; FDA approved; Fibroblasts; Fishes; Folic Acid; Genes; Goals; HK2 gene; Hereditary Disease; In Vitro; Investigation; Kidney; Kidney Failure; Knowledge; LDL-Receptor Related Protein 2; Lead; Length; Ligands; Light; Link; Lipids; Liquid substance; Mediating; Medicine; Membrane; Mental Retardation; Mutate; Mutation; Neurologic; Normal Cell; Oculocerebrorenal Syndrome; Other Genetics; Outcome; Patients; Penetrance; Pharmaceutical Preparations; Pharmacotherapy; Phase; Phenotype; Phosphoric Monoester Hydrolases; Proteins; Renal function; Risk; Role; Safety; Scheme; Severities; Signal Transduction; Sirolimus; Symptoms; Testing; Texas red; Therapeutic; Toxicology; Transcription Factor AP-2 Alpha; Variant; Vesicle; Zebrafish; cell motility; ciliopathy; design; disease-causing mutation; drug candidate; in vivo; induced pluripotent stem cell; kidney cell; mutant; novel; precision medicine; receptor; response; solute; targeted agent; therapy design; trafficking; uptake

Lowe Syndrome (LS) is a lethal genetic disease described in the early fifties; however, no specific treatment against this devastating condition is available to affected children. However, this project aims to change that unfortunate situation. Specifically, we recently found that LS abnormalities can be reversed by repositioning two FDA-approved drugs currently used for other indications. Our lab previously established that LS patient cells exhibit two phenotype categories: RhoGTPase signaling abnormalities and primary cilia assembly defects. Therefore, using LS patient cells, we tested FDA- approved drugs for their ability to revert these phenotypes and identified two medicine groups as suppressors of LS patient abnormalities. However, the impact that different OCRL1 patient mutations have on the penetrance of each phenotype category and on the drug response is still unknown. Here we hypothesize that different OCRL1 patient mutations have differential impact on Ocrl1 biochemical activities and in consequence lead to diverse phenotype category penetrance and sensitivity to anti-LS drugs. This project’s goal is to test this hypothesis and the ability of the compounds to revert phenotypes associated with renal failure in kidney cells in vivo and in vitro. We will pursue the following specific aims: Aim 1. To determine the effect of different OCRL1 patient mutations on LS phenotype category severity and on candidate drug-mediated phenotype suppression. Aim 2. To determine the impact of different OCRL1 patient mutations on Ocrl1 biochemical activity. Aim 3. To test different drug therapy schemes for suppression of renal abnormalities in a LS animal model. This project has high significance as it will produce a novel LS theoretical framework and it will address the lack of therapeutic approaches designed to suppress the causes of LS. Importantly, the candidate drugs are currently used in children to ameliorate other conditions and can be readily repurposed to LS (i.e., known safety and low risk of adverse toxicology). Therefore, the translational potential and impact of this project is very high. Further, since our investigations unveiled that LS shares some characteristics with other genetic diseases such as ciliopathies, these discoveries may also impact patients suffering other conditions besides LS.

Lowe综合征（LS）是五十年代初描述的致命遗传疾病。但是，没有具体的 受影响的儿童可针对这种破坏性状况进行治疗。但是，这个项目旨在 改变这种不幸的情况。具体而言，我们最近发现LS异常可以被逆转 重新定位目前用于其他适应症的两种FDA批准的药物。 我们的实验室先前确定LS患者细胞暴露了两个表型类别：Rhogtpase 信号异常和原发性纤毛组装缺陷。因此，使用LS患者细胞，我们测试了FDA- 批准的药物能够恢复这些表型并确定两个药物组为补充 LS患者异常。但是，不同的OCRL1患者突变对 每个表型类别和药物反应的渗透性仍然未知。在这里我们假设 不同的OCRL1患者突变对OCRL1生化活动和在 后果导致潜水员表型类别的渗透率和对抗LS药物的敏感性。这 项目的目标是检验该假设以及化合物恢复与表型相关的表型的能力 体内和体外肾细胞中的肾衰竭。我们将追求以下具体目标： 目标1。确定不同OCRL1患者突变对LS表型类别严重程度的影响 候选药物介导的表型抑制。 目标2。确定不同OCRL1患者突变对OCRL1生化活性的影响。 目的3。测试不同的药物治疗方案，以抑制LS动物模型中的肾脏异常。 该项目具有很高的意义，因为它将产生一个新颖的LS理论框架，它将 解决缺乏旨在抑制LS原因的治疗方法。重要的是， 候选药物目前用于儿童改善其他疾病，很容易 重新使用为LS（即已知的安全性和低毒理学风险）。因此，翻译 该项目的潜力和影响很高。此外，自从我们的调查揭示了LS股票 某些具有其他遗传疾病（例如纤毛病）的特征，这些发现也可能影响 除LS以外，患者患有其他疾病。