{"doi":"10.1101/2021.10.05.463243","title":"Peripherally targeted analgesia via AAV-mediated sensory neuron-specific inhibition of multiple pronociceptive sodium channels in rat","abstract":"Abstract This study reports that targeting intrinsically disordered regions (IDRs) of Na V 1.7 protein facilitated discovery of sodium channel inhibitory peptide aptamers (NaviPA) for adeno-associated virus (AAV)-mediated, sensory neuron-specific analgesia. A multipronged inhibition of I Na1.7 , I Na1.6 , and I Na1.3 , but not I Na1.5 and I Na1.8 was found for a prototype, named NaviPA1, which was derived from the Na V 1.7 intracellular loop 1 and is conserved among the TTXs Na V subtypes. NaviPA1 expression in primary sensory neurons (PSNs) of dorsal root ganglia (DRG) produced significant inhibition of TTXs I Na but not TTXr I Na . 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 Na V s has potential as peripheral nerve-restricted analgesic therapeutics.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":226923,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9558,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":811059,"name":"Brandon Itson-Zoske","orcid":"0000-0003-2979-7386","position":1,"is_corresponding":false},{"id":830301,"name":"Chensheng Qiu","orcid":"0000-0002-0973-9026","position":2,"is_corresponding":false},{"id":830302,"name":"Mahmudur Rahman","orcid":"0000-0003-3981-7619","position":3,"is_corresponding":false},{"id":830762,"name":"Uarda Gani","orcid":null,"position":4,"is_corresponding":false},{"id":304960,"name":"Fan Fan","orcid":"0000-0003-1463-3610","position":5,"is_corresponding":false},{"id":276991,"name":"Theodore Cummins","orcid":"0000-0001-9509-6380","position":6,"is_corresponding":false},{"id":679840,"name":"Quinn H. Hogan","orcid":"0000-0002-5445-5276","position":7,"is_corresponding":false},{"id":304957,"name":"Hongwei Yu","orcid":"0000-0003-3029-3644","position":8,"is_corresponding":false},{"id":422317,"name":"Seung Min Shin","orcid":"0000-0003-3509-8389","position":0,"is_corresponding":true}],"reference_count":168,"raw_metadata":null,"created_at":"2026-07-18T23:54:38.004707Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}