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 慢性疼痛是疼痛，持续到正常的康复时间。 15亿人 全球遭受慢性疼痛的困扰，随着老年人口的增长 生长，糖尿病的患病率上升，癌症存活率提高。慢性疼痛不仅 严重影响许多患者的日常生活质量，这也使社会经济重大 社会负担。由于可用的有效治疗选项数量有限，慢性 尽管有成瘾和副作用的风险，但通常会用阿片类药物治疗疼痛。不幸的是， 处方阿片类药物以治疗慢性疼痛，这在很大程度上加剧了当前的阿片类药物流行。 因此，紧急而明显的未满足的需要非依恋的替代性镇痛药 慢性疼痛的治疗。推动开发特定和非依恋的替代方案的推动力 止痛药引起了特定的钠通道NAV1.7的兴趣，这对 疼痛感。 NAV1.7的功能收益突变与特征的疾病有关 通过肢体强烈的燃烧疼痛：原发性红血球。相反，功能丧失 NAV1.7导致无法感到疼痛。因此，抑制nav1.7可能是有效的 减轻疼痛和治疗红细胞痛患者的方法。为此，我们设计了 表观遗传调节剂抑制NAV1.7的表达。而不是永久编辑 这些表观遗传调节剂的基因组将瞬时抑制NAV1.7的表达。通过定位 NAV1.7在DNA级时，我们可以实现NAV1.7的特定而持久的调制，并使用 比RNA和蛋白质靶向方法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输送以达到高度 特异性和功效。此外，我们将在小规模中评估我们的优化调节器 在大型动物模型中制造研究以及毒理学研究。结果 研究将是一种优化的基因疗法，不仅是非副词和有效治疗的 慢性疼痛，但也高度持久。