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.

纤毛病是一组超过 100 种由纤毛缺陷引起的重叠临床疾病。初级纤毛及其锚定结构，基体。虽然个体很少见，但这组显着增加了人口遗传疾病负担，一些估计表明其总发病率高达1：1000。重要的是，尽管有些纤毛病是致命的，大多数患者存活到成年，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、神经认知障碍缺陷、肥胖、糖尿病和精神疾病。目前尚无治疗方法和最少的姑息治疗选择。该提案旨在迈出开发临床的第一步渴望减缓或阻止纤毛病病理退行性方面的资产。我们的工作是基于两个关键观察结果。首先，最近的几项研究表明纤毛病蛋白质调节选择性蛋白酶体介导的信号成分降解。其次，最近在人类细胞中进行的全基因组抑制筛选表明，去泛素酶 USP35 可以改善纤毛病引起的信号传导缺陷。正在验证这些观察发现，Bardet-Biedl 的三个斑马鱼模型中 USP35 的抑制或删除综合征（BBS），一种纤毛病模型，减弱了几种特征性表型，大多数光感受器有明显的结构和运输缺陷，没有明显的毒副作用影响。这些发现和模型为 Rescindo 的形成奠定了基础 Therapeutics 是一家生物技术公司，其使命是开发抑制屏幕和衍生分子作为合理的治疗剂。在过去的一年里，雷辛多开发了两种具有潜在临床用途的试剂：表达腺相关病毒针对人和小鼠 USP35 的 shRNA 及其反义寡核苷酸目标。在这里，我们的目标是测试这些工具在人类细胞和小鼠模型中的实用性设计临床试验的序言。在我们公司内部，我们将测试每种方法的功效减弱来自突变患者的原代细胞中的旁分泌信号传导的试剂三个不同的 BBS 基因。与此同时，与 Arshavsky 实验室合作杜克大学，我们将测试每种试剂是否可以在减弱或消除 BBS 小鼠模式中光感受器的逐渐丧失。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这将是开发第一个纤毛病治疗资产的关键一步。