Initial efforts of translational development of AAV-encoded NaViPA1 for peripherally targeted analgesia in neuropathic pain.

We previously reported the discovery of a multipronged sodium channel-inhibitory peptide aptamer (NaViPA1), derived from the intracellular disordered sequence conserved among tetrodotoxin-sensitive (TTXs) sodium channels (NaVs), for adeno-associated virus (AAV)-mediated sensory neuron-targeted analgesia in rat models of chronic pain. In this study, an initial translational effort was undertaken, including (1) removing GFP from the AAV transgene cassette and enhancing small peptide NaViPA1 molecular engagement by constructing a concatemeric NaViPA1 (CoNaViPA1) containing two copies of consensus NaViPA1 as a tandem repeat and (2) evaluating long-lasting preclinical analgesic effectiveness in rats by injecting AAV-CoNaViPA1 into the sciatic nerve in a rat model of tibial nerve injury-induced painful neuropathy. Results showed analgesic efficacy that persisted for 3-4 months of observation, with magnitudes and time courses comparable between male and female rats. AAV genome analysis confirmed the peripheral nerve-restricted biodistribution of AAV-CoNaViPA1 and long-term transgene expression. Inhibition of TTXs NaVs and suppression of action potential firing by CoNaViPA1 were demonstrated in human sensory ganglion neurons, underscoring the translational potential of AAV-mediated CoNaViPA1 expression in the peripheral sensory pathway for treating intractable chronic neuropathic pain conditions resistant to current therapies.