Preclinical optimization of a gene therapy for erythromelalgia and chronic pain

红斑性肢痛症和慢性疼痛基因疗法的临床前优化

• 批准号: 10855356
• 负责人: Fernando Aleman Guillen
• 金额: $ 114.95万
• 依托单位: NAVEGA THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10855356
• 关键词: Affect; Analgesics; Animal Model; Antibodies; Binding; Biological Assay; Burning Pain; CRISPR-mediated transcriptional activation; CRISPR/Cas technology; Cell Line; Cells; Chromatography; Clinical Trials; Congenital Pain Insensitivity; DNA; Dependovirus; Development; Diabetes Mellitus; Disease; Dose; Drug Kinetics; Economic Burden; Elderly; Engineering; Epigenetic Process; Erythromelalgia; Evaluation; Failure; Feasibility Studies; Genome; Goals; Guide RNA; Harvest; Human; Human Cell Line; In Vitro; Libraries; Limb structure; Methods; Molecular; Molecular Conformation; Mus; Mutation; Neurons; Opioid; Organ; Pain; Pain management; Pathway interactions; Patients; Peptides; Persistent pain; Persons; Pharmaceutical Preparations; Phase; Plasmids; Population; Prevalence; Proteins; Quality of life; RNA; Reagent; Repression; Risk; Safety; Societies; Sodium Channel; Specificity; Spinal Ganglia; Survival Rate; System; Testing; Therapeutic; Time; Toxic effect; Toxicology; Transcription Repressor; Transfection; Transgenes; Translating; Tropism; Variant; Zinc Fingers; addiction; alternative treatment; animal efficacy; animal safety; cancer survival; cellular transduction; chronic pain; chronic pain management; clinical development; density; design; dosage; drug development; efficacious treatment; efficacy evaluation; epigenome; gain of function mutation; gene therapy; healing; improved; induced pluripotent stem cell; innovation; interest; lead candidate; lead optimization; loss of function; manufacture; nonhuman primate; novel; novel therapeutics; opioid epidemic; pain reduction; pain relief; pre-clinical; prescription opioid; promoter; rational design; response; restraint; safety study; screening; side effect; small molecule inhibitor; socioeconomics; transgene expression

ABSTRACT Chronic pain is pain that persists past the normal time of healing. 1.5 billion people worldwide suffer from chronic pain and this number continues to increase as the elderly population grows, the prevalence of diabetes rises, and cancer survival rates improve. Chronic pain not only severely impacts daily quality of life for many patients, it also places a heavy socioeconomic burden on society. Due to the limited number of efficacious treatment options available, chronic pain is often treated with opioids despite the risk of addiction and side effects. Unfortunately, the prescribing of opioids to treat chronic pain has largely fueled the current opioid epidemic. Therefore, there is an urgent and clear unmet need for non-addictive alternative analgesics for the treatment of chronic pain. The push to develop specific and non-addictive alternative painkillers has brought interest to a particular sodium channel, NaV1.7, shown to be important for pain sensing. Gain-of-function mutations in NaV1.7 are associated with a disorder characterized by intense burning pain in the extremities: primary erythromelalgia. Conversely, loss-of function of NaV1.7 results in the inability to feel pain. Therefore, inhibiting NaV1.7 can be an effective method of reducing pain and treat erythromelalgia patients. To accomplish this, we designed epigenetic modulators to repress expression of NaV1.7. Rather than making permanent edits to the genome, these epigenetic modulators will transiently inhibit expression of NaV1.7. By targeting NaV1.7 at the DNA-level, we can achieve specific and long-lasting modulation of NaV1.7, with better pharmacokinetics prospects than RNA- and protein-targeting approaches. In this study, we propose to optimize these epigenetic modulators as well as their delivery in order to achieve high specificity and efficacy. In addition, we will evaluate our optimized modulators in small-scale manufacturing studies as well as toxicological studies in a large animal model. The result of this study will be an optimized gene therapy that is not only non-addictive and efficacious for treatment of chronic pain but also highly specific and long-lasting.

抽象的 慢性疼痛是指在正常愈合时间之后持续存在的疼痛。 15亿人 全世界都有慢性疼痛患者，并且随着老年人口的增加，这一数字持续增加 增长，糖尿病患病率上升，癌症存活率提高。不仅是慢性疼痛 严重影响了许多患者的日常生活质量，也给社会经济带来了沉重的负担 社会负担。由于可用的有效治疗方案数量有限，慢性病 尽管存在成瘾和副作用的风险，但通常使用阿片类药物治疗疼痛。不幸的是， 开阿片类药物治疗慢性疼痛在很大程度上助长了当前阿片类药物的流行。 因此，对于非成瘾性替代镇痛药的迫切且明显的未满足需求 慢性疼痛的治疗。推动开发特定且不成瘾的替代品 止痛药引起了人们对特定钠通道 NaV1.7 的兴趣，该通道被证明对 疼痛感应。 NaV1.7 的功能获得突变与以下疾病相关： 四肢剧烈烧灼痛：原发性红斑性肢痛。反之，功能丧失 NaV1.7 导致无法感觉疼痛。因此，抑制NaV1.7可能是一种有效的方法。 减轻疼痛和治疗红斑性肢痛症患者的方法。为了实现这一目标，我们设计了 表观遗传调节剂抑制 NaV1.7 的表达。而不是进行永久编辑 在基因组中，这些表观遗传调节剂将暂时抑制 NaV1.7 的表达。通过定位 在DNA水平上NaV1.7，我们可以实现对NaV1.7的特异性和持久的调节， 比 RNA 和蛋白质靶向方法具有更好的药代动力学前景。在这项研究中，我们 建议优化这些表观遗传调节剂及其递送，以实现高 特异性和有效性。此外，我们还将小规模评估我们优化的调制器 大型动物模型中的制造研究以及毒理学研究。这样的结果 研究将是一种优化的基因疗法，不仅不会成瘾，而且对治疗有效 慢性疼痛，但也具有高度特异性和持久性。