From Pain Resilience Genes Toward Therapeutic, Non-Opiate Modulation: An iPSC-Based Approach

安全有效地治疗慢性疼痛是一种未得到满足的医疗需求，这反过来又促进了 阿片类药物危机。痛苦的体验因人而异，有些人对 比起其他人更痛苦。虽然在临床上观察到了疼痛的个体差异，但尚未发现 在实验室中精确建模，也没有仔细检查其机械基础。这是部分原因 因为疼痛涉及到周围神经系统的检测和中枢神经系统的感知 可能受到许多因素的调节，包括遗传、表观遗传、环境和社会因素。我们的 遗传性红斑性肢痛症(IEM)的血缘关系研究 相同的Nav1.7突变(S241T)使我们能够识别在 在这些患者中，感觉神经元使用完整的外显子测序作为疼痛的调节器。在这项提案中，我们 将建立在我们发现的“疼痛恢复基因”的基础上，并评估药理学的潜力 KV7通道调节剂降低人类遗传性感觉神经元的超兴奋性 经过验证的慢性疼痛受试者，作为确定安全有效的策略的一种方式，避免 阿片类药物在慢性疼痛治疗中的应用

Safe and effective treatment for chronic pain is an unmet medical need, which in turn has contributed to the opioid crisis. The experience of pain varies from person to person, with some individuals relatively resilient to pain compared to others. Individual-to-individual variation in pain, while observed in the clinics, has not been accurately modeled in the laboratory nor has its mechanistic underpinnings carefully examined. This is partially because pain involves detection by the peripheral nervous system and perception in the central nervous system, and may be modulated by many factors including genetic, epigenetic, environmental and social. Our studies of blood relatives with inherited erythromelalgia (IEM) with varying degrees of pain despite carrying the same Nav1.7 mutation (S241T) have allowed us to identify modulatory gene variants/mutations expressed in sensory neurons using whole exome sequencing as modulators of pain in these patients. In this proposal, we will build upon our discovery of “pain resilience genes” and evaluate the potential of pharmacological modulators of Kv7 channels to reduce hyperexcitability of human sensory neurons derived from genetically validated subjects with chronic pain, as a way to identify safe and effective strategies that steer away from opioids in the treatment of chronic pain.