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：
9917402
负责人：
Michelle L Hastings
金额：
$ 57.21万
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/9917402
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 protein 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 Modeling 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 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 病是一种致命的溶酶体贮积症 (LSD)，由常染色体隐性突变引起在 CLN3 中，该疾病从幼儿期视力丧失进展为癫痫、运动能力下降、认知能力下降。残疾和痴呆，典型预期寿命为 15-30 岁 CLN3 Batten 无法治愈。唯一可用的治疗方法可以解决某些疾病症状，但不能延缓疾病进展。由于缺乏对 CLN3 Batten 的了解，阻碍了对 CLN3 Batten 的有效治疗的发现。该提案的目标是蛋白质的功能和导致神经变性的潜在机制。测试采用反义寡核苷酸（ASO）的 CLN3 Batten 治疗方法，并在此过程中，阐明这种疾病的神经变性机制，为研究和发现有效性提供信息 Batten 病和其他 LSD 的治疗大多数 CLN3 Batten 病例是由外显子 7 缺失引起的。和 8 (CLN3Δ78)，这会导致开放阅读框移位和提前终止密码子。使用 ASO 重定向前 mRNA 剪接并纠正 CLN3Δ78 mRNA 的阅读框将部分恢复蛋白质功能并对CLN3 Batten病有治疗作用。研究结果支持我们的假设，即恢复 CLN3Δ78 阅读框可缓解功能障碍我们将在拟议的项目中检验我们的假设。目的是 1) 比较野生型和新型 CLN3 亚型的功能，2) 开发一种方法使用 ASO 增加 CLN3Δex78 同工型，3) 使用人类评估 ASO 对 CLN3 Batten 病的治疗总的来说，这项研究将使我们能够建立 CLN3 Batten 病的细胞系以及小鼠和 4) 猪模型。更好地了解 CLN3 蛋白的功能以及 ASO 在治疗 CLN3 Batten 病中的效用。