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 慢性疼痛是疼痛，持续到正常的康复时间。全球15亿人 患有慢性疼痛，随着老年人口的增长，这一数字继续增加， 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，对 疼痛感。 NAV1.7的功能性突变与罕见疾病有关 具有强烈疼痛的特征，例如原发性红细胞毛和小纤维的患者 神经病。此外，已显示NAV1.7表达水平在各种疼痛中增加 状况。相反，NAV1.7功能丧失导致无法感到疼痛。所以， 抑制NAV1.7可以是减轻疼痛和治疗慢性患者的有效方法 疼痛。为此，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编辑 抑制NAV1.7的表达。通过针对DNA级别的NAV1.7，我们可以实现特定的 NAV1.7的长期调节，具有更好的药代动力学前景 定位方法。这种创新的方法已被证明可以预防和逆转急性 和五个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奇 除了其高水平的特异性和功效，该项目的目标是支持业务 开发活动，找到一个有力的伴侣，将这种疗法带给数百万患者 这需要用于慢性疼痛的非副词，有效和持久的治疗方法。