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ResearchIn-Press PreviewNeuroscienceTherapeutics Open Access | 10.1172/JCI170813
1Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, United States of America
2Department of Physiology, Medical College of Georgia, Augusta, United States of America
3Department of Biology, School of Science, Indiana University-Purdue University, Indianapolis, United States of America
4Department of Orthopedic Surgery, Qingdao Municipal Hospital, Qingdao, China
Find articles by Shin, S. in: JCI | PubMed | Google Scholar
1Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, United States of America
2Department of Physiology, Medical College of Georgia, Augusta, United States of America
3Department of Biology, School of Science, Indiana University-Purdue University, Indianapolis, United States of America
4Department of Orthopedic Surgery, Qingdao Municipal Hospital, Qingdao, China
Find articles by Itson-Zoske, B. in: JCI | PubMed | Google Scholar
1Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, United States of America
2Department of Physiology, Medical College of Georgia, Augusta, United States of America
3Department of Biology, School of Science, Indiana University-Purdue University, Indianapolis, United States of America
4Department of Orthopedic Surgery, Qingdao Municipal Hospital, Qingdao, China
Find articles by Fan, F. in: JCI | PubMed | Google Scholar |
1Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, United States of America
2Department of Physiology, Medical College of Georgia, Augusta, United States of America
3Department of Biology, School of Science, Indiana University-Purdue University, Indianapolis, United States of America
4Department of Orthopedic Surgery, Qingdao Municipal Hospital, Qingdao, China
Find articles by Xiao, Y. in: JCI | PubMed | Google Scholar
1Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, United States of America
2Department of Physiology, Medical College of Georgia, Augusta, United States of America
3Department of Biology, School of Science, Indiana University-Purdue University, Indianapolis, United States of America
4Department of Orthopedic Surgery, Qingdao Municipal Hospital, Qingdao, China
Find articles by Qiu, C. in: JCI | PubMed | Google Scholar
1Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, United States of America
2Department of Physiology, Medical College of Georgia, Augusta, United States of America
3Department of Biology, School of Science, Indiana University-Purdue University, Indianapolis, United States of America
4Department of Orthopedic Surgery, Qingdao Municipal Hospital, Qingdao, China
Find articles by Cummins, T. in: JCI | PubMed | Google Scholar
1Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, United States of America
2Department of Physiology, Medical College of Georgia, Augusta, United States of America
3Department of Biology, School of Science, Indiana University-Purdue University, Indianapolis, United States of America
4Department of Orthopedic Surgery, Qingdao Municipal Hospital, Qingdao, China
Find articles by Hogan, Q. in: JCI | PubMed | Google Scholar
1Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, United States of America
2Department of Physiology, Medical College of Georgia, Augusta, United States of America
3Department of Biology, School of Science, Indiana University-Purdue University, Indianapolis, United States of America
4Department of Orthopedic Surgery, Qingdao Municipal Hospital, Qingdao, China
Find articles by Yu, H. in: JCI | PubMed | Google Scholar
Published May 9, 2024 - More info
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.