Reading Frame Correction for the Treatment of Batten Disease

阅读框架校正治疗 Batten 病

基本信息

批准号：
10383400
负责人：
Michelle L Hastings
金额：
$ 55.58万
依托单位：
ROSALIND FRANKLIN UNIV OF MEDICINE & SCI
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：
2020-05-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10383400
关键词：
Address Affect Age Age-Years Alternative Splicing Amino Acid Sequence Animal Model Antisense Oligonucleotides Base Sequence Behavior Biological Assay Biological Markers Biology Blindness Brain C-terminal CLN3 gene Cell model Cells Cessation of life Child Childhood Clinical Trials Cognitive Data Dementia Disease Disease Progression Disease model Dose Ensure Exons Eye Family suidae Functional disorder Genes Goals Health Human Human Cell Line In Vitro Investigational Drugs Label Length Life Life Expectancy Lysosomal Storage Diseases Mediating Messenger RNA Motor Mus Mutate Mutation Nerve Degeneration Neurologic Neurons Open Reading Frames Pathology Patients Pharmacodynamics Production Protein Isoforms Proteins RNA Splicing Reading Frames Recovery Research Retina Scientist Seizures Spielmeyer-Vogt Disease Symptoms Terminator Codon Testing Therapeutic Therapeutic Effect Tissues Translating Transmembrane Domain Vision base cognitive disability disease phenotype early childhood effective therapy human model improved in vitro activity in vivo in vivo monitoring innovation mRNA Precursor mouse model mutant neuropathology new therapeutic target novel novel strategies porcine model preclinical development preclinical efficacy premature protein function standard of care success therapeutic development therapeutic target tool trafficking treatment strategy

项目摘要

CLN3 Batten disease is a fatal lysosomal storage disorder (LSD) resulting from autosomal recessive mutations in CLN3. The disease progresses from vision loss in early childhood to seizures, motor decline, cognitive disability and dementia, with a typical life expectancy of 15-30 years of age. There is no cure for CLN3 Batten and the only treatments available address some disease symptoms, but do not delay disease progression. The discovery of an effective treatment for CLN3 Batten has been hindered by a lack of understanding of the protein's function and the underlying mechanisms leading to neurodegeneration. The goal of this proposal is to test a therapeutic approach for CLN3 Batten that employs antisense oligonucleotides (ASOs) and in so doing, elucidate mechanisms of neurodegeneration in this disease that will inform research and discovery of effective treatments for Batten diseases and other LSDs. Most cases of CLN3 Batten are caused by deletion of exons 7 and 8 (CLN3Δ78), which results in an open reading frame shift and a premature termination codon. We hypothesize that using ASOs to redirect pre-mRNA splicing and correct the reading frame of CLN3Δ78 mRNA will partially restore protein function and have a therapeutic effect in CLN3 Batten disease. Our preliminary findings support our hypothesis, demonstrating that restoring the CLN3Δ78 reading frame alleviates dysfunction associated with disease in both cell and animal models. We will test our hypothesis in the proposed project with the aims to 1) compare the function of the wild type and novel CLN3 isoforms, 2) develop an approach using ASOs to increase CLN3Δex78 isoforms, 3) assess ASO treatments for CLN3 Batten disease using human cell lines as well as mouse and 4) porcine models of CLN3 Batten disease. Collectively, this study will allow us to better understand the function of the CLN3 protein and the utility of ASOs in treating CLN3 Batten disease.

CLN3 Batten病是由常染色体隐性突变引起的致命溶酶体储存障碍（LSD）在Cln3中。该疾病从幼年时期的视力丧失发展到癫痫发作，运动衰落，认知能力残疾和痴呆症，典型的预期寿命为15-30岁。无法治愈CLN3板条而且唯一可用的治疗方法解决了一些疾病症状，但不要延迟疾病的进展。这缺乏了解蛋白质的功能和导致神经退行性的潜在机制。该提议的目的是测试员工反义寡核苷酸（ASO）的CLN3板的治疗方法阐明这种疾病中神经退行性的机制，这些机制将为研究和发现提供有效的研究板条疾病和其他LSD的治疗方法。大多数CLN3板条的病例是由删除外显子7引起的和8（CLN3Δ78），这会导致开放的阅读框架移动和过早的终止密码子。我们假设使用ASO重定向前mRNA剪接并纠正CLN3Δ78mRNA的读取框架将部分恢复蛋白质功能，并对CLN3板条疾病具有治疗作用。我们的初步发现支持我们的假设，证明恢复CLN3Δ78阅读框架减轻功能障碍与细胞和动物模型中的疾病相关。我们将在拟议项目中检验我们的假设以1）比较野生型和新型CLN3同工型的功能，2）开发一种方法使用ASO提高CLN3ΔEX78同工型，3）使用人类的CLN3 Batten疾病评估ASO治疗细胞系以及小鼠和4）CLN3板条疾病的猪模型。总的来说，这项研究将使我们为了更好地了解CLN3蛋白的功能以及ASO在治疗CLN3 Batten疾病中的效用。