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J. Clin. Invest., May 09 2024, e170813 | https://doi.org/10.1172/JCI170813
Peripherally targeted analgesia via AAV-mediated sensory neuron-specific inhibition of multiple pronociceptive sodium channels
Seung Min Shin1, Brandon Itson-Zoske1, Fan Fan2, Yucheng Xiao3, Chensheng Qiu1,4, Theodore R. Cummins3, Quinn H. Hogan1, and Hongwei Yu1*
1Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, WI 53226
2Department of Physiology, Medical College of Georgia, Augusta University, Augusta, GA 30912
3Department of Biology, School of Science, Indiana University-Purdue University, Indianapolis, IN, 46202
4Department of Orthopedic Surgery, Qingdao Municipal Hospital, Qingdao, China 266011
*Corresponding author : Hongwei Yu
Abstract
This study reports that targeting intrinsically disordered regions of NaV1.7 protein facilitates discovery of sodium channel inhibitory peptide aptamers (NaViPA) for adeno-associated virus (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, 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. Immunohistochemistry 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 peripheral nerve-restricted analgesic therapeutics.
논문정보
- Research article
- 2024년 05월 (BRIC 등록일 2024-05-14)
- 국외 연구진
- 의약학 > 신경의학
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