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

 描述(申请人提供)：神经性疼痛是一个严重的健康问题，影响着全球数百万人，发生在多达7%的总人口中。患者神经病理性疼痛的管理是复杂的，估计有40%-60%的人对现有的止痛治疗无效。人口老龄化、糖尿病流行以及癌症和艾滋病患者的大量涌入都导致了顽固性神经性疼痛的流行。大量受影响的人突出了开发治疗这种疾病的新疗法的迫切需要。MRGPR(MRG/SNSR)家族的G蛋白偶联受体(GPCRs)在背根节表达，在伤害性感觉的调节中发挥重要作用。鞘内注射内源性多肽BAM8-22可通过激活人类mRgprX1同源基因(小鼠：mrgprC11，大鼠：mrgprC)来减轻啮齿动物模型中的神经病理性疼痛。然而，治疗效果是短暂的。On Target Treateutics倡导了一项新技术，以开发稳定、长效的GPCRs多肽调节剂。这些类似物是多肽-连接物-脂质结合物，它们被膜锚定，以提供高效和长期稳定的局部活性。我们已经修改了内源性BAM8-22，以产生一种更高效力的类似物，它锚定在细胞膜上，并提供局部活性。在目标1中，我们建议通过修改我们已经确定的特定氨基酸来产生更稳定的类似物。在目标2中，这些“脂化稳定的BAM”结构将在神经病理性疼痛(慢性收缩损伤)的小鼠模型中进行测试。完成这些特定的目标将导致选择一个特征良好的候选化合物进行进一步开发。第二阶段的研究将集中在毒理学、剂量、给药方式，以及在更大的动物模型中测试稳定的BAM类似物。第一阶段的工作将在On Target Treateutics与我们在塔夫茨医学中心(Alan Kopin博士)和约翰霍普金斯大学(董新忠博士)的研究伙伴一起进行。

 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).