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Developing the first TPI Df therapeutics

开发第一个 TPI Df 疗法

基本信息

批准号：
10613470
负责人：
Michael John Palladino
金额：
$ 53.85万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-15 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10613470
关键词：
Acute Amino Acid Substitution Anemia Animal Model Animals Behavioral Biological Assay Blood Brain Brain Injuries Catalogs Cell Culture Techniques Cell Line Cell model Cells Cessation of life Chemicals Childhood Chronic Clinical Clinical Trials Clustered Regularly Interspaced Short Palindromic Repeats Collection Data Databases Defect Development Diagnosis Disease Dose Drosophila genus Drug usage Enzymes Exhibits FDA approved Fibroblasts Foundations Functional disorder Genetic Goals Heterozygote Human Image Impairment In Vitro Inpatients Intervention Isomerase Knockout Mice Lead Libraries Library Collection Development Liver Longevity Mammals Mediating Metabolic Metabolic Diseases Methodology Missense Mutation Modeling Motor Mus Muscle Mutation Neurologic Neuromuscular Diseases Optics Paralysed Pathogenesis Pathogenicity Pathway interactions Patients Pharmaceutical Preparations Pharmacotherapy Pilot Projects Proteasome Inhibitor Proteins Quality Control Research Severity of illness Solid Structure-Activity Relationship Symptoms System Testing Therapeutic Therapeutic Agents Toxic effect Toxicology Triose-Phosphate Isomerase Ubiquitin United States National Institutes of Health Universities Validation analog combinatorial chemistry design early childhood efficacy testing efficacy validation fly high throughput screening human disease immunocytochemistry in vivo insertion/deletion mutation lead series liver metabolism member mouse model multicatalytic endopeptidase complex mutant neuromuscular novel novel therapeutics pharmacologic premature protein degradation protein function response small molecule small molecule libraries transmission process

项目摘要

Abstract/Project summary: TPI Df is a devastating untreatable childhood metabolic disease resulting in anemia, paralysis, irreversible brain damage and premature death. Numerous single amino acid substitutions in Triosephosphate Isomerase (TPI) are pathogenic and result in rapidly progressing multisystem disease. Importantly, all known pathogenic TPI Df mutations result in a protein that retains function and pathogenesis is known to result from increased turnover of the functioning protein by Protein Quality Control pathways (PQC). We have developed a human cellular TPI Df assay based on a cellular model of the “common” E104D mutation and implemented it for high-content, high-throughput imaging. We have used this model in a pilot screen and validated its utility to identify novel compounds that modulate mutant TPI protein levels in human cells. We propose to develop the assay to full HTS standards, conduct a screen of several relevant compound libraries, and identify first-in-class TPI Df small molecule therapies. We will validate hits in secondary assays for TPI stability and activity in TPI Df patient cells, prioritize them in a panel of in vitro toxicology and metabolic stability assays, examine structure activity relationships (SARs) of the lead compounds and substantially validate them in vivo using a recently developed mouse TPI Df model. Overall this project will discover and validate the first ever treatments for TPI Df that will provide the basis for clinical trials.

摘要/项目摘要： TPI Df是一种毁灭性的不可治疗的儿童代谢性疾病，可导致贫血、瘫痪、不可逆脑损伤和过早死亡磷酸丙糖中的许多单个氨基酸取代异构酶（TPI）是致病性的，并导致快速进展的多系统疾病。重要的是所有已知的致病性TPI Df突变导致蛋白质保留功能，并且已知发病机制通过蛋白质质量控制途径（PQC）增加功能蛋白的周转。我们基于“常见”E104 D突变的细胞模型，开发了人细胞TPI Df试验并将其用于高内容、高通量成像。我们已经在一个试点屏幕中使用了这个模型并验证了其在鉴定调节人细胞中突变TPI蛋白水平的新化合物方面的效用。我们建议将检测方法开发为完整的HTS标准品，对几种相关化合物进行筛选库，并确定一流的TPI Df小分子疗法。我们将在第二阶段验证命中率 TPI Df患者细胞中TPI稳定性和活性的测定，在体外毒理学组中对其进行优先排序和代谢稳定性测定，检查先导化合物的结构活性关系（SAR），使用最近开发的小鼠TPI Df模型在体内基本上验证了它们。总体而言，该项目将发现并验证TPI Df的首次治疗方法，为临床试验提供基础。