Lipidated Stable BAM8-22 Offers a Promising Therapeutic for Neuropathic Pain

脂化稳定 BAM8-22 为神经性疼痛提供了一种有前景的治疗方法

• 批准号: 9045171
• 负责人: ALAN S KOPIN
• 金额: $ 22.39万
• 依托单位: ON TARGET THERAPEUTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-03-01 至 2018-08-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9045171
• 关键词: Acquired Immunodeficiency Syndrome; Adverse reactions; Affect; Agonist; Amino Acids; Analgesics; Animal Model; Animals; Attention; Attenuated; Biological Assay; CMKLR1 gene; Cell membrane; Cellular Membrane; Chronic; Complex; Development; Diabetes Mellitus; Diffusion; Disease; Dose; Drug Delivery Systems; Drug Kinetics; Epidemic; Family; G-Protein-Coupled Receptors; General Population; Health; Human; Hypersensitivity; In Vitro; Individual; Intractable Pain; Intrathecal Injections; Laboratories; Life; Ligands; Lipids; Malignant Neoplasms; Medical; Medical center; Membrane; Methods; Minor; Modification; Molecular Biology; Morphine; Mus; Nociception; Orthologous Gene; Pain; Patients; Peptide Hydrolases; Peptides; Pharmaceutical Preparations; Phase; Play; Positioning Attribute; Prevalence; Rattus; Recombinants; Refractory; Research; Resistance; Rodent Model; Role; Site; Spinal Ganglia; Structure; Technology; Testing; Therapeutic; Therapeutic Effect; Time; Toxic effect; Toxicology; Universities; aging population; analog; base; chemical synthesis; chronic constriction injury; cohort; drug candidate; experience; in vivo; mechanical allodynia; mouse model; new technology; novel; novel strategies; novel therapeutics; painful neuropathy; peptide analog; phase 1 study; phase 2 study; prototype; public health relevance; receptor; targeted treatment

 DESCRIPTION (provided by applicant): Neuropathic pain is a serious health problem that affects millions of people worldwide and occurs in as much as 7% of the general population. The management of neuropathic pain in patients is complex with an estimated 40-60% of individuals refractory to existing analgesic therapies. The aging population, the diabetes epidemic, and the significant cohorts of cancer and AIDS patients all contribute to the prevalence of intractable neuropathic pain. The large number of affected individuals highlights the pressing need to develop novel therapeutics for this condition. The Mrgpr (Mrg/SNSR) family of G protein-coupled receptors (GPCRs) are expressed in the dorsal root ganglia and play an important role in the modulation of nociception. Intrathecal administration of the endogenous peptide BAM8-22 attenuates neuropathic pain in rodent models through activation of the human MrgprX1 ortholog (mouse: MrgprC11, rat: MrgprC). The therapeutic effects, however, are short lived. On Target Therapeutics has championed a novel technology to develop stable, long acting peptide modulators of GPCRs. These analogs are peptide-linker-lipid conjugates that are membrane anchored to provide local activity with high potency and long-term stability. We have modified endogenous BAM8-22 to generate a higher potency analog that anchors into the cellular membrane and provides local activity. In Aim 1, we propose to generate more stable analogs by modifying specific amino acids that we have already identified. In Aim 2, these 'lipidated stable BAM' constructs will be tested in a mouse model of neuropathic pain (chronic constriction injury). Completion of these Specific Aims will result in th selection of a well-characterized candidate compound for further development. Phase II studies will focus on toxicology, dosing, mode of administration, and testing of the stable BAM analog in a larger animal model. The Phase I efforts will be performed at On Target Therapeutics in conjunction with our research partners at Tufts Medical Center (Dr. Alan Kopin) and Johns Hopkins University (Dr. Xinzhong Dong).

 描述（由申请人提供）：神经性疼痛是一种严重的健康问题，影响全球数百万人，发生在多达7%的普通人群中。患者神经性疼痛的管理是复杂的，估计有40-60%的个体对现有的镇痛治疗难治。人口老龄化、糖尿病流行以及癌症和艾滋病患者的显著群体都导致了难治性神经性疼痛的流行。大量受影响的个体突出了迫切需要为这种情况开发新的治疗方法。G蛋白偶联受体（GPCRs）的Mrgpr（Mrg/SNSR）家族在背根神经节中表达，并且在伤害感受的调节中起重要作用。鞘内施用内源性肽BAM 8 -22通过激活人MrgprX 1直系同源物（小鼠：MrgprC 11，大鼠：MrgprC）减轻啮齿动物模型中的神经性疼痛。然而，治疗效果是短暂的。On Target Therapeutics倡导了一种新技术，用于开发稳定、长效的GPCR肽调节剂。这些类似物是肽-接头-脂质缀合物，其被膜锚定以提供具有高效力和长期稳定性的局部活性。我们已经修饰了内源性BAM 8 -22以产生更高效力的类似物，其锚定到细胞膜中并提供局部活性。在目标1中，我们提出通过修饰我们已经鉴定的特定氨基酸来产生更稳定的类似物。在目标2中，这些“脂化稳定BAM”构建体将在神经性疼痛（慢性压迫性损伤）的小鼠模型中进行测试。这些特定目标的完成将导致选择充分表征的候选化合物用于进一步开发。II期研究将重点关注毒理学、剂量、给药方式以及在更大的动物模型中对稳定的BAM类似物进行测试。第一阶段的工作将在On Target Therapeutics与我们在塔夫茨医学中心（Alan Kopin博士）和约翰霍普金斯大学（Xinzhong Dong博士）的研究合作伙伴一起进行。