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Proteolipid protein suppression for Pelizaeus Merzbacher Disease

蛋白脂质蛋白抑制治疗梅兹巴赫病

基本信息

批准号：
10044262
负责人：
Paul Joseph Tesar
金额：
$ 33.77万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-15 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10044262
关键词：
3-Dimensional Adult Age Antisense Oligonucleotides Axon Behavioral Biological Brain CRISPR/Cas technology Cell Line Cessation of life Childhood DNA Sequence Rearrangement Data Deterioration Development Developmental Delay Disorders Disease Disease Progression Disease model Dose Ensure Exhibits Failure Foundations Frequencies Functional disorder Gene Proteins Genes Genomics Genotype Head Hereditary Disease Heterogeneity Histologic Human In Vitro Individual Jimpy Mice Knock-out Lead Link Longevity Measures Mediating Membrane Messenger RNA Motor Mus Mutation Myelin Myelin Proteins Nervous System Physiology Neural Conduction Neuraxis Neurodegenerative Disorders Neurologic Neurologic Dysfunctions Oligodendroglia Onset of illness Pathology Patients Pelizaeus-Merzbacher Disease Pharmaceutical Preparations Pharmacodynamics Phase Phased Innovation Awards Phenotype Point Mutation Production Proteins Proteolipids Regimen Structure Tail Testing Therapeutic Therapeutic Effect Tissues Toxic effect Variant Work X Chromosome brain cell clinical phenotype comparative disease phenotype early childhood efficacy study efficacy testing gain of function gain of function mutation genomic locus human pluripotent stem cell improved in vitro Model in vivo in vivo evaluation induced pluripotent stem cell leukodystrophy mortality motor behavior motor impairment mouse model mutant myelination novel pharmacodynamic biomarker postnatal prevent rare genetic disorder response therapeutic development therapeutic evaluation therapeutic target

项目摘要

SUMMARY Pelizaeus-Merzbacher disease (PMD) is a severe X-linked pediatric neurodegenerative disorder impacting myelination in the central nervous system (CNS). PMD results from toxic gain of function mutations in the PLP1 gene which encodes the most prevalent myelin protein, proteolipid protein, of the CNS. PMD exhibits a spectrum of clinical phenotypes that reflect wide genotypic heterogeneity. The majority of PLP1 variants, including supernumerary copies and various point mutations, lead to progressive neurological deterioration and death, often during childhood. However, PLP1-null patients and mice display comparatively mild phenotypes, suggesting that reduction of aberrant PLP1 expression might provide a therapeutic strategy across PMD genotypes. In this proposal we will quantify the biological activity of antisense oligonucleotides (ASOs) to target and suppress aberrant proteolipid protein and measure the resulting therapeutic effect in PMD mouse (in vivo) and human (in vitro) models. During the R61 phase we will use proteolipid protein levels as a pharmacodynamic marker to inform dose ranges and regimens of ASOs. Additionally, we will measure variability of phenotypic endpoints in PMD models to ensure that all efficacy studies are appropriately powered. In the R33 phase, we will test the in vivo efficacy of ASOs to suppress proteolipid protein and enhance myelination and neurological function in a genomically accurate duplication mouse model of PMD. Additionally, we will test the efficacy of ASOs to suppress proteolipid protein and enhance human oligodendrocyte survival and function in oligocortical spheroids (organized 3D human CNS tissue-like structures) from a comprehensive panel of characterized induced pluripotent stem cell lines from PMD patients. Collectively, these studies will demonstrate whether PLP1-targeting ASOs have sufficient biological activity to warrant continued therapeutic development.

总结 Pelizaeus-Merzbacher病（PMD）是一种严重的X连锁儿科神经退行性疾病，中枢神经系统（CNS）的髓鞘形成。PMD是由细胞中的毒性功能突变引起的。 PLP 1基因编码CNS中最普遍的髓鞘蛋白，蛋白脂质蛋白。PMD展示了反映广泛基因型异质性的临床表型谱。大多数PLP 1变体，包括多余拷贝和各种点突变，导致进行性神经功能恶化，死亡，往往在童年。然而，PLP 1缺失的患者和小鼠显示出相对温和的表型，提示PLP 1异常表达的减少可能提供一种治疗PMD的策略，基因型在该提案中，我们将定量反义寡核苷酸（ASO）的生物活性，靶向并抑制异常蛋白脂质蛋白，并测量PMD小鼠中产生的治疗效果（在体内）和人（体外）模型。在R61阶段，我们将使用蛋白脂质蛋白水平作为药效学标志物，以告知ASO的剂量范围和方案。此外，我们将测量 PMD模型中表型终点的变异性，以确保所有疗效研究具有适当的把握度。在R33阶段，我们将测试ASO抑制蛋白脂质蛋白和增强细胞凋亡的体内功效。在PMD的基因组精确复制小鼠模型中的髓鞘形成和神经功能。此外，本发明还我们将测试ASO抑制蛋白脂质蛋白和增强人类少突胶质细胞存活的功效。从一个全面的研究中，一组来自PMD患者的表征的诱导多能干细胞系。这些研究将证明PLP 1靶向ASO是否具有足够的生物活性以保证持续治疗发展