Optimization of a Gene Therapy for Chronic Pain in Human DRGs

人类 DRG 慢性疼痛基因疗法的优化

基本信息

批准号：
10259387
负责人：
Fernando Aleman Guillen
金额：
$ 27.54万
依托单位：
NAVEGA THERAPEUTICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-22 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10259387
关键词：
Adult Affect American Antibodies Binding Biological Assay Biotechnology Businesses CRISPR/Cas technology Calcium Cell Line Centers for Disease Control and Prevention (U.S.)Congenital Pain Insensitivity Data Dependovirus Development Electrophysiology (science)Environment Future Genes Genetic Genetic study Goals Guide RNA Health Human Human Cell Line Image In Vitro Inherited Measures Methods Modeling Molecular Conformation Mus Mutation Narcotics Neurons Nociception Opioid Orthologous Gene Paclitaxel Pain Pain management Patients Pharmaceutical Preparations Phase Phenotype Protein Engineering Protein Isoforms Proteins Repression Research Personnel Risk Rodent Small Business Innovation Research Grant Sodium Channel Specificity Spinal Ganglia Streptococcus pyogenes System Testing Therapeutic Translating Treatment Failure Variant Western Blotting Zinc Fingers addiction alternative treatment base cellular transduction chemotherapy chronic pain chronic pain patient clinical translation design drug development electric field gene therapy genome-wide in vivo in vivo evaluation inhibitor/antagonist innovation loss of function mutation mouse model novel therapeutics pain model pain relief pain signal painful neuropathy pre-clinical rare genetic disorder side effect single-cell RNA sequencing small molecule inhibitor transcriptome sequencing vector voltage

项目摘要

Project Summary/Abstract The goal of this project is design and optimize a gene therapy product that relieves pain in a non- permanent, non-addictive and long lasting manner. There are more than 100 million Americans suffering from chronic pain and current treatments consist mainly of opioid narcotics. However, opioids have severe side effects and are highly addictive. Voltage-gated sodium channels transmit pain signals in nociceptive neurons. Genetic studies have correlated a rare hereditary loss-of-function mutation in one channel isoform (NaV1.7) with a rare genetic disorder known as Congenital Insensitivity to Pain (CIP). Thus, selective repression of NaV1.7 could recapitulate the phenotype of CIP. However, the high homology of human NaV proteins, have frustrated most efforts to develop selective inhibitors. We have developed an innovative gene therapy approach to target NaV1.7 in vivo, and have demonstrated its efficacy in three murine models of pain. During this Phase I SBIR, we will optimize this gene therapy to target the human NaV1.7 sequence in human cell lines, and then we will choose the best designs to test them in human DRG neurons for potency, specificity, and efficacy in an ex vivo chemotherapy-induced neuropathic pain model. Thus, Navega’s final goal is to develop novel therapeutics that can mitigate pain through the use of specific gene therapy approaches to provide an alternative treatment to opioids for chronic pain.

项目摘要/摘要该项目的目的是设计和优化基因疗法产品，该产品可以挽救非 - 永久，非副词和持久的方式。有超过1亿美国人患有慢性疼痛和当前治疗方法主要由阿片类药物组成。然而，阿片类药物具有严重的副作用，并且具有很高的添加剂。电压门控钠通道在伤害感受神经元中传递疼痛信号。遗传研究与罕见的遗传有关一个通道同工型（NAV1.7）的功能丧失突变，罕见的遗传疾病被称为先天性对疼痛不敏感（CIP）。那就是，nav1.7的选择性表达可以概括 CIP的表型。但是，人类NAV蛋白的高同源性最沮丧开发选择性抑制剂的努力。我们已经开发了一种创新的基因治疗方法在体内靶向NAV1.7，并在三种鼠疼痛模型中证明了其效率。期间这阶段I SBIR，我们将优化这种基因疗法，以靶向人类NAV1.7序列人类细胞系，然后我们将选择最佳的设计来测试人类DRG神经元在体内化学疗法引起的神经性疼痛模型中的效力，特异性和效率。那就是，纳维加的最终目标是开发新的疗法，可以通过使用来减轻疼痛特定基因疗法的方法，为阿片类药物提供替代治疗方法疼痛。