Acid Sphingomyelinase and Niemann-Pick Disease
酸性鞘磷脂酶和尼曼匹克病
基本信息
- 批准号:9247906
- 负责人:
- 金额:$ 42.38万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-06-23 至 2022-05-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAnimalsApplications GrantsCeramidaseCessation of lifeChimeric ProteinsClinicalComplementary DNADNADataDevelopmentDiseaseDoseEnzymesFUS-1 ProteinFundingFutureGene TransferGenesGoalsGrantHeat shock proteinsHemorrhageHepatotoxicityHumanIntercellular adhesion molecule 1InvestigationKnock-outKnockout MiceLeadLipidsLiverLiver diseasesLungLysosomal Storage DiseasesMusMutationNiemann-Pick DiseasesOrganOutcomePathogenesisPathogenicityPathologyPatientsProductionPublicationsRecombinantsResearchResidual stateSPHK1 enzymeSourceSphingosineSpleenStem cell transplantTestingTissuesToxic effectVisceralWorkacid sphingomyelinasebasecell typeclinically relevanteffective therapyenzyme replacement therapyexperimental studygene therapyimprovedin vivomouse modelnovelnovel markernovel strategiesnovel therapeuticsphase 1 studyphase 2 studypre-clinicalpreclinical evaluationpreclinical toxicityprogramsscreeningsphingosine kinasesphingosine-1-phosphate lyasetherapy developmentuptakevector
项目摘要
DESCRIPTION (provided by applicant):
The overall goal of this research is to use our unique mouse models of Types A & B Niemann-Pick disease (NPD) to develop new therapies for this disorder and to uncover novel pathogenic mechanisms. Two aims are proposed. Aim 1: Preclinical Evaluation of Two New Therapies. In the first set of studies we will evaluate a novel enzyme enhancement approach using the heat shock protein, Hsp70. These experiments are based on a recent publication showing that Hsp70 enhanced residual ASM activity and reduced lysosomal pathology in cells from Type A and B NPD patients, a finding that has been supported by new in vivo data obtained since the previous submission. The second set of studies will continue our work aimed at improved delivery of ASM to the lung using ICAM-1. A "proof-of-principle" gene transfer experiment will be undertaken that will use AAV8 vectors to express ASM/ICAM-1 fusion proteins in the livers of NPD mice. Uptake and efficacy of the fusion enzymes in the lung and other clinically important organs will be studied. New in vivo data also has been obtained to demonstrate the feasibility of this approach. Aim 2: Investigation of Novel Pathogenic Mechanisms Leading to ERT-Related Liver Toxicity. Preclinical ERT studies in ASM knockout (ASMKO) mice have shown that administration of recombinant ASM at doses above 5 mg/Kg results in liver bleeding, the release of liver enzymes, and death. We have recently found that sphingosine, not sphingomyelin, is the major accumulating lipid in the livers of these mice, and hypothesize that sphingosine storage is responsible, at least in part, for the ERT-associated toxicity. We will determine the source of accumulating sphingosine by evaluating the expression of ceramidases, sphingosine kinases and sphingosine-1-phosphate lyase in the ASMKO mice, and breed these animals to mice lacking sphingosine kinase-1 to determine the effects on ERT- associated liver toxicity. These results should provide a mechanistic basis for the clinical observations in the mice, and also may lead to new strategies to overcome this toxicity.
描述(由申请人提供):
这项研究的总体目的是使用我们独特的A&B Niemann-Pick疾病类型的小鼠模型来开发这种疾病的新疗法并发现新颖的致病机制。提出了两个目标。目标1:两种新疗法的临床前评估。在第一组研究中,我们将使用热休克蛋白HSP70评估一种新型的酶增强方法。这些实验基于最近的出版物表明,HSP70增强了A型和B型NPD患者细胞中细胞中的残留ASM活性,并降低了溶酶体病理,这一发现得到了自上次提交以来获得的新的体内数据支持的发现。第二组研究将继续我们的工作,旨在使用ICAM-1改善ASM向肺部的交付。将进行“原理证明”基因转移实验,该实验将使用AAV8矢量在NPD小鼠肝脏中表达ASM/ICAM-1融合蛋白。将研究融合酶在肺和其他临床上重要的器官中的摄取和功效。还获得了新的体内数据,以证明这种方法的可行性。 AIM 2:研究导致与ERT相关的肝毒性的新型致病机制的研究。 ASM敲除(ASMKO)小鼠的临床前ERT研究表明,以高于5 mg/kg的剂量给予重组ASM导致肝脏出血,肝酶的释放和死亡。我们最近发现,鞘氨醇,而不是鞘磷脂是这些小鼠肝脏中的主要积聚脂质,并假设鞘氨醇的储存至少部分是由于ERT相关的毒性。我们将通过评估ASMKO小鼠中神经酰胺酶,鞘氨酸激酶和鞘氨酸-1-磷酸裂解酶的表达来确定积累鞘氨醇的来源,并将这些动物培养为缺乏鞘氨醇激酶-1的小鼠,以确定对ERT-相关肝毒性的影响。这些结果应为小鼠的临床观察提供机械基础,并可能导致克服这种毒性的新策略。
项目成果
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Endocannabinoid-Based Treatment for the Neurologic Niemann-Pick Diseases
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- 批准号:
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$ 42.38万 - 项目类别:
Acid Ceramidase, Ceramide and Farber Disease
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8035557 - 财政年份:2000
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$ 42.38万 - 项目类别:
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