Advancing precision pain medicines to the clinic

将精准止痛药推向临床

• 批准号: 10822921
• 负责人: Fernando Aleman Guillen
• 金额: $ 40万
• 依托单位: NAVEGA THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-22 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10822921
• 关键词: Acute Pain; Affect; Analgesics; Animal Model; Antibodies; Binding; Budgets; Businesses; CRISPR/Cas technology; Carrageenan; Chemotherapy-induced peripheral neuropathy; Clinic; Congenital Pain Insensitivity; DNA; Dependovirus; Development; Diabetes Mellitus; Drug Kinetics; Economic Burden; Elderly; Ensure; Epigenetic Process; Erythromelalgia; Failure; Fiber; Freund' s Adjuvant; Genome; Goals; Grant; Guide RNA; K/BxN model; Leadership; Medicine; Methods; Modeling; Molecular Conformation; Mus; Mutation; Neurons; Neuropathy; Nociception; Opioid; Pain; Pain management; Patients; Persistent pain; Persons; Pharmaceutical Preparations; Pharmacologic Substance; Population; Pre-Clinical Model; Prevalence; Proteins; Quality of life; RNA; Rare Diseases; Repression; Rheumatoid Arthritis; Risk; Societies; Sodium Channel; Specificity; Spinal Ganglia; Survival Rate; System; Therapeutic; Time; Transcription Repressor; Translating; Variant; Zinc Fingers; addiction; alternative treatment; cancer survival; central pain; chronic pain; chronic pain management; chronic pain patient; clinical development; design; drug development; efficacious treatment; epigenome; gain of function mutation; gene therapy; healing; improved; inflammatory pain; innovation; intense pain; interest; loss of function; meetings; novel; novel therapeutics; opioid epidemic; pain model; pain reduction; pain relief; prescription opioid; prevent; programs; side effect; small molecule inhibitor; socioeconomics

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 rare disorder characterized by intense pain, such as in patients with primary erythromelalgia and small-fiber neuropathy. Additionally, NaV1.7 expression levels have been shown to increase in various pain conditions. 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 treating patients with chronic pain. 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. This innovative approach has been shown to prevent and reverse acute and chronic pain in five preclinical models of pain. Given the exciting novelty of this approach, in addition to its high level of specificity and efficacy, the goal of this project is to support the business development activities in finding a strong partner to bring this therapy to the millions of patients that need non-addictive, efficacious, and long-lasting treatments for chronic pain.

摘要 慢性疼痛是指持续超过正常愈合时间的疼痛。全球有15亿人 患有慢性疼痛，随着老年人口的增长，这一数字还在继续增加， 糖尿病患病率上升，癌症存活率提高。慢性疼痛不仅 严重影响了许多患者的日常生活质量，也给社会经济造成了沉重的负担 给社会带来负担。由于可用有效治疗选择的数量有限，慢性 疼痛通常用阿片类药物治疗，尽管有成瘾和副作用的风险。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目前的阿片类药物流行。 因此，对非成瘾性替代镇痛剂的需求迫切且明显未得到满足。 慢性疼痛的治疗。推动开发特定的、不会上瘾的替代品 止痛药引起了人们对一种特殊的钠通道Nav1.7的兴趣，它被证明对 疼痛感应。NAV1.7基因功能获得突变与罕见疾病相关 以剧烈疼痛为特征的，如在原发性红斑性肢痛症和纤维细小的患者中 神经病。此外，研究表明，Nav1.7的表达水平在各种疼痛中都会增加 条件。相反，Nav1.7功能丧失会导致感觉不到疼痛。因此， 抑制Nav1.7是一种有效的减轻疼痛和治疗慢性阻塞性肺疾病患者的方法 疼痛。为了实现这一点，我们设计了表观遗传调节器来抑制Nav1.7的表达。 这些表观遗传调节器不是对基因组进行永久性编辑，而是暂时的 抑制Nav1.7的表达。通过在DNA级别瞄准Nav1.7，我们可以实现特定和 Nav1.7的长期调节，具有比RNA和蛋白质更好的药代动力学前景- 有针对性的方法。这一创新的方法已被证明可以预防和扭转急性呼吸道感染 以及五种临床前疼痛模型中的慢性疼痛。考虑到这种方法令人兴奋的新颖性，在 除了它的高水平的特异性和有效性，这个项目的目标是支持业务 在寻找强有力的合作伙伴将这种疗法带给数百万患者方面的开发活动 需要对慢性疼痛进行非上瘾、有效和持久的治疗。