Developing a new therapeutic agent for retinal ciliopathies

开发一种新的视网膜纤毛病治疗剂

基本信息

批准号：
9567640
负责人：
NICHOLAS KATSANIS
金额：
$ 2.39万
依托单位：
RESCINDO THERAPEUTICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-30 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9567640
关键词：
Ablation Adolescent Adult Adverse effects Anatomy Antisense Oligonucleotides Attenuated Bardet-Biedl Syndrome Biochemical Biotechnology Cell Fractionation Cell model Cells Cilia Clinical Clinical Trials Clinical Trials Design Collaborations Data Defect Dependovirus Development Diabetes Mellitus Disease Embryo Felis catus Fibroblasts Foundations Functional disorder Future Genes Goals Health Hereditary Disease Human Human Genetics Incidence Individual Intervention Kidney Kidney Failure Laboratories Larva Lead Measurement Measures Mediating Medicine Mental disorders Mission Modeling Mus Mutant Strains Mice Mutate Mutation Neonatal Neurocognitive Obesity Organ Organelles Paracrine Communication Parents Pathology Pathway interactions Patients Peptide Hydrolases Phenotype Photoreceptors Population Genetics Primates Proteins RNA interference screen Reagent Research Personnel Retina Retinal Retinal Degeneration Rhodopsin Signal Transduction Signal Transduction Pathway Site Skin Structure Suppressor Genes Symptoms Technology Testing Therapeutic Therapeutic Agents Therapeutic Effect Therapeutic Intervention Time Tissues Toxicity Tests Translations Ubiquitin Universities Validation Western Blotting Work Zebrafish base burden of illness ciliopathy clinical development design drug discovery efficacy testing genome-wide in vivo interest kinetosome metabolic phenotype mouse model multicatalytic endopeptidase complex mutant notch protein novel novel therapeutics palliative photoreceptor degeneration pre-clinical prevent small hairpin RNA therapeutic candidate therapeutic target tool trafficking vector

项目摘要

The ciliopathies are a group of >100 overlapping clinical disorders caused by defects in the primary cilium and its anchoring structure, the basal body. Although individually rare, this group contributes significantly to the population genetic disease burden, with some estimates placing their combined incidence to as much as 1:1000. Importantly, although some ciliopathies are lethal, most patients survive to adulthood, where they are faced with profound clinical challenges of managing multiple symptoms that include retinal degeneration, neurocognitive defects, obesity, diabetes and psychiatric illness. At present, there are no treatments and minimal palliative options. This proposal aims to take the first steps towards developing clinical assets that aspire to slow or arrest degenerative aspects of the ciliopathy pathology. Our work is grounded on two key observations. First, several recent studies have shown that ciliopathy proteins regulate the selective proteasome-mediated degradation of signaling components. Second, a recent genome-wide suppressor screen in human cells showed that suppression of the deubiquitinase USP35 could ameliorate ciliopathy-induced signaling defects. Validating these observations, suppression or deletion of USP35 in three zebrafish models of Bardet-Biedl syndrome (BBS), a model ciliopathy, attenuated several pathognomonic phenotypes, most prominently structural and trafficking defects in the photoreceptor with no apparent toxic side effects. These discoveries and models have been foundational to the formation of Rescindo Therapeutics, a biotech company whose mission is to develop suppressor screens and derivative molecules as rational therapeutic agents. During the past year, Rescindo has developed two reagents of potential clinical utility: an adeno-associated virus expressing shRNAs against human and mouse USP35 and antisense oligonucleotides against the same target. Here, we aim to test the utility of these tools in human cells and in mouse models as a pre-amble to designing clinical trials. Within our company, we will test the efficacy of each reagent to attenuate paracrine signaling in primary cells derived from patients with mutations in three different BBS genes. In parallel, and in collaboration with the Arshavsky laboratory at Duke, we will test whether each reagent can have a quantitative benefit in attenuating or extinguishing the progressive loss of photoreceptors in a mouse mode of BBS. Successful completion of these studies will provide the necessary data for the rational design of future trials and will represent a key step towards developing the first therapeutic assets for ciliopathies.

纤毛病是由缺陷引起的一组> 100个重叠的临床障碍原发性纤毛及其锚定结构，基底体。虽然个别稀有，但对人口遗传疾病负担有重大贡献，一些估计置于他们的合并发病率高达1：1000。重要的是，尽管有些纤毛病是致命的，大多数患者幸存到成年，在那里他们面临着深刻的临床管理多种症状的挑战，包括视网膜变性，神经认知缺陷，肥胖，糖尿病和精神病。目前，没有治疗最小的姑息治疗选择。该建议旨在迈出开发临床的第一步渴望减慢或阻止纤毛病理学的退化方面的资产。我们的工作是基于两个关键观察。首先，最近的一些研究表明纤毛病蛋白质调节信号分量的选择性蛋白酶体介导的降解。第二，在人类细胞中，最近全基因组抑制筛查表明抑制去泛素酶USP35可以改善纤毛病诱导的信号传导缺陷。验证在三种斑马鱼模型中，这些观察结果，抑制或删除了usp35 综合征（BBS），一种模型纤毛病，衰减了几种病理学表型，大多数表型光感受器中的结构和贩运缺陷显着，没有明显的有毒面效果。这些发现和模型是基础的基础 Therapeutics，一家生物技术公司，其使命是开发抑制器屏幕和衍生物分子作为理性治疗剂。在过去的一年中，Rescindo有开发了潜在临床实用性的两种试剂：一种表达腺相关的病毒针对人和小鼠USP35的shRNA和反义寡核苷酸针对同一核苷酸目标。在这里，我们旨在测试人类细胞和鼠标模型中这些工具的实用性预先设计临床试验。在我们公司内，我们将测试每个的功效试剂可减弱来自具有突变患者的原代细胞中的旁分泌信号传导三个不同的BBS基因。并行，并与Arshavsky实验室合作杜克，我们将测试每种试剂在衰减或在BB的小鼠模式下熄灭了光感受器的进行性丧失。成功的这些研究的完成将为未来试验的合理设计提供必要的数据并将代表开发纤毛病的第一个治疗资产的关键步骤。