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.

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。全球15亿人 患有慢性疼痛，并且随着老年人口的增长，这个数字继续增加， 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 的功能获得突变与罕见疾病相关 以剧烈疼痛为特征，例如原发性红斑性肢痛症和小纤维痛患者 神经病。此外，NaV1.7 表达水平已被证明在各种疼痛中增加 状况。相反，NaV1.7 功能丧失会导致无法感觉疼痛。所以， 抑制 NaV1.7 可能是减轻疼痛和治疗慢性病患者的有效方法 疼痛。为了实现这一目标，我们设计了表观遗传调节剂来抑制 NaV1.7 的表达。 这些表观遗传调节剂不会对基因组进行永久性编辑，而是会短暂地 抑制NaV1.7的表达。通过在 DNA 水平上靶向 NaV1.7，我们可以实现特异性和 NaV1.7 的持久调节，比 RNA 和蛋白质具有更好的药代动力学前景 目标定位方法。这种创新方法已被证明可以预防和逆转急性 和五种临床前疼痛模型中的慢性疼痛。鉴于这种方法令人兴奋的新颖性， 除了其高水平的特异性和有效性之外，该项目的目标是支持业务 寻找强有力的合作伙伴将这种疗法带给数百万患者的开发活动 需要非成瘾性、有效且持久的慢性疼痛治疗方法。