Targeting STAU1 for TDP-43 proteinopathies

靶向 STAU1 治疗 TDP-43 蛋白病

基本信息

批准号：
10512615
负责人：
Stefan M. PULST
金额：
$ 38.37万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10512615
关键词：
ALS patients Age Aging Amyotrophic Lateral Sclerosis Antisense Oligonucleotides Autophagocytosis Bacterial Artificial Chromosomes Biological Assay Cells Chemicals Chemistry Data Development Disease Disease model Dose Fibroblasts Financial Hardship Frequencies Future Genes Genetic Grant Health High Pressure Liquid Chromatography Histologic Human In Vitro Injections Investigation LY6E gene Lead Measures Methods Modeling Modification Molecular Motor Motor Cortex Motor Neurons Mus Nerve Degeneration Neurodegenerative Disorders Pathologic Patients Phase Phenotype Population PrP Preparation Proteins Purkinje Cells Solubility Spinal Cord Structure-Activity Relationship Synapses Therapeutic Toxic effect Transgenic Mice United States National Institutes of Health Validation Vertebral column Work acute toxicity base efficacy study efficacy testing experience improved in vivo in vivo Model knock-down molecular phenotype motor behavior mouse model nervous system disorder neurodegenerative phenotype phase I trial phosphorothioate protein TDP-43 protein aggregation protein biomarkers screening sporadic amyotrophic lateral sclerosis success therapeutic target uptake

项目摘要

Project Summary/Abstract Our U01 CREATE grant supported development of BIIB105, an ATXN2 antisense oligonucleotide (ASO) for treatment that is now in a phase 1 trial for amyotrophic lateral sclerosis (ALS). We are now proposing to expand the ATXN2 target space by developing ASOs to STAU1. STAU1 interacts with ATXN2, and is overabundant in multiple in vitro and in vivo models of neurodegeneration. Our proof-of-concept data showed positive PD efficacy, in that lowering STAU1 modifies disease-related phenotypes. ATXN2[Q127] SCA2 mice haploinsufficient for Stau1 had normalized cerebellar gene and autophagy protein abundances, ATXN2 protein aggregates were eliminated, and motor behavior was improved. In addition, the abnormally slow intrinsic Purkinje cell (PC) firing frequency in SCA2 mice is restored following Stau1 ASO treatment. STAU1 expands the ATXN2 target space and may prove more effective as a therapeutic target for ALS and other TDP-43 proteinopathies as its protein abundance is increased 3-4 fold in multiple in vitro and in vivo neurodegenerative models including sporadic ALS spinal cord. We have already screened for ASOs targeting STAU1, identifying 10 top leads that lower STAU1 expression by 90-99% in SCA2 patient fibroblasts, including two potent ASOs that also target mouse Stau1 invaluable for in vivo efficacy studies in disease models. Our overall objective is to optimize ASO sequence and chemistry for lowering STAU1 expression, and to refine an in vivo efficacy models for characterizing target engagement and PD/PK parameters in vivo. Currently, no therapeutics exist that significantly modify sporadic ALS. STAU1 is overabundant in multiple neurodegenerative disease models, and Stau1 knockdown by genetic interaction improves in vivo phenotypes. The R61 phase of our study will span one year and is organized in two aims: Aim 1 will prepare sequence optimized chemically-modified ASOs for efficacy testing in BAC-STAU1 mice and Prp-TDP43Q331K mice. Aim 2 refines the use of Prp-TDP43Q331K mice for characterizing efficacy of STAU1 ASO, resulting in optimal doses required for effective STAU1 knockdown and phenotype modification. The R33 phase spans the remaining two years of the study and is comprised of two additional aims: Aim 3 will demonstrate that lead ASOs modify TDP-43 abundance & solubility, normalizes autophagy markers, histological phenotypes and motor neuron counts and motor behavior of Prp-TDP43Q331K mice. Aim 4 will determine ASO effects for improving survival for three most efficacious lead ASOs using Prp- TDP43WTxQ331K double transgenic mice. The terminal milestone for this study will be validation of in vivo efficacy for three optimized ASOs with long duration of action for Staufen knockdown, and efficacy data for additional ASO sequences useful or future investigation. The crucial objective is the identification of lead STAU1 ASOs that modify an ALS neurodegenerative phenotype suitable for advancing to a URGenT or Blueprint Neurotherapeutics Network (BPN) application to the NIH. Ultimately, our study will significantly expand therapeutic targets for ALS and other neurodegenerative diseases.

项目概要/摘要我们的 U01 CREATE 资助支持 BIIB105 的开发，BIIB105 是一种 ATXN2 反义寡核苷酸 (ASO)，用于该疗法目前正处于针对肌萎缩侧索硬化症（ALS）的一期试验中。我们现在建议扩大通过将 ASO 开发为 STAU1 来确定 ATXN2 目标空间。 STAU1 与 ATXN2 相互作用，并且在多种神经退行性变的体外和体内模型。我们的概念验证数据显示出积极的 PD 功效，因为降低 STAU1 可以改变疾病相关的表型。 ATXN2[Q127] SCA2 小鼠 Stau1 的单倍体不足，小脑基因和自噬蛋白丰度、ATXN2 蛋白均已标准化聚集物被消除，运动行为得到改善。此外，异常缓慢的内在 Stau1 ASO 治疗后，SCA2 小鼠的浦肯野细胞 (PC) 放电频率恢复。 STAU1 扩展了 ATXN2 靶向空间，可能被证明作为 ALS 和其他 TDP-43 的治疗靶点更有效蛋白质病，因为其蛋白质丰度在多种体外和体内神经退行性疾病中增加了 3-4 倍模型包括散发性 ALS 脊髓。我们已经筛选了针对 STAU1 的 ASO，确定了 10 个顶级先导药物可将 SCA2 患者成纤维细胞中 STAU1 表达降低 90-99%，其中包括两个有效的 ASO 它还针对小鼠 Stau1，这对于疾病模型的体内功效研究非常有价值。我们的总体目标是优化 ASO 序列和化学以降低 STAU1 表达，并完善体内功效模型用于表征体内目标参与和 PD/PK 参数。目前，尚无治疗方法可以显着改善散发性 ALS。 STAU1 在多种神经退行性疾病模型中过多，并且通过遗传相互作用敲低 Stau1 可改善体内表型。我们研究的 R61 阶段将跨越一个年，有两个目标：目标 1 将制备序列优化的化学修饰 ASO BAC-STAU1 小鼠和 Prp-TDP43Q331K 小鼠的功效测试。目标 2 改进 Prp-TDP43Q331K 小鼠的使用用于表征 STAU1 ASO 的功效，从而获得有效 STAU1 敲低所需的最佳剂量和表型修饰。 R33 阶段跨越研究的剩余两年，包括两个额外目标：目标 3 将证明先导 ASO 可以改变 TDP-43 丰度和溶解度，标准化 Prp-TDP43Q331K 的自噬标记物、组织学表型、运动神经元计数和运动行为老鼠。目标 4 将确定 ASO 对使用 Prp- 提高三种最有效的主要 ASO 生存率的影响 TDP43WTxQ331K双转基因小鼠。这项研究的最终里程碑将是验证体内功效三种优化的 ASO 具有较长的作用持续时间，可实现诗道芬击倒，以及额外的功效数据 ASO 序列有用或未来的研究。关键目标是识别主要 STAU1 ASO 修改 ALS 神经退行性表型，适合推进到 URGenT 或蓝图向 NIH 申请神经治疗网络 (BPN)。最终，我们的研究将显着扩展 ALS 和其他神经退行性疾病的治疗靶点。