PDF(Pubmed)
Abstract：
This study reports that targeting intrinsically disordered regions of the voltage-gated sodium channel 1.7 (NaV1.7) protein facilitates discovery of sodium channel inhibitory peptide aptamers (NaViPA) for adeno-associated virus-mediated (AAV-mediated), sensory neuron-specific analgesia. A multipronged inhibition of INa1.7, INa1.6, INa1.3, and INa1.1 - but not INa1.5 and INa1.8 - was found for a prototype and named NaViPA1, which was derived from the NaV1.7 intracellular loop 1, and is conserved among the TTXs NaV subtypes. NaViPA1 expression in primary sensory neurons (PSNs) of dorsal root ganglia (DRG) produced significant inhibition of TTXs INa but not TTXr INa. DRG injection of AAV6-encoded NaViPA1 significantly attenuated evoked and spontaneous pain behaviors in both male and female rats with neuropathic pain induced by tibial nerve injury (TNI). Whole-cell current clamp of the PSNs showed that NaViPA1 expression normalized PSN excitability in TNI rats, suggesting that NaViPA1 attenuated pain by reversal of injury-induced neuronal hypersensitivity. IHC revealed efficient NaViPA1 expression restricted in PSNs and their central and peripheral terminals, indicating PSN-restricted AAV biodistribution. Inhibition of sodium channels by NaViPA1 was replicated in the human iPSC-derived sensory neurons. These results summate that NaViPA1 is a promising analgesic lead that, combined with AAV-mediated PSN-specific block of multiple TTXs NaVs, has potential as a peripheral nerve-restricted analgesic therapeutic.
摘要：
这项研究报道，靶向NaV1.7蛋白的内在无序区域有助于发现腺相关病毒（AAV）介导的钠通道抑制肽适体（NaViPA），感觉神经元特异性镇痛。对INa1.7、INa1.6、INa1.3和INa1.1的多管齐下抑制。但没有发现INA1.5和INA1.8的原型，命名为NaViPA1，它来自NaV1.7胞内环1，在TTXsNaV亚型中保守。背根神经节（DRG）的初级感觉神经元（PSNs）中的NaViPA1表达对TTXsINa产生了显着抑制作用，但对TTXrINa没有抑制作用。DRG注射AAV6编码的NaViPA1可显着减弱由胫神经损伤（TNI）引起的神经性疼痛的雄性和雌性大鼠的诱发和自发疼痛行为。PSN的全细胞电流钳显示NaViPA1表达可使TNI大鼠的PSN兴奋性正常化，表明NaViPA1通过逆转损伤诱导的神经元超敏反应来减轻疼痛。免疫组织化学显示，在PSN及其中枢和外周末端中，NaViPA1的有效表达受到限制，表明PSN限制的AAV生物分布。NaViPA1对钠通道的抑制在人iPSC衍生的感觉神经元中复制。这些结果总结了NaViPA1是一种有前途的镇痛药物，结合AAV介导的PSN特异性阻断多个TTXsNavs，具有作为周围神经限制镇痛疗法的潜力。
