5R33NS116203-03: Primary sensory neuron-targeted block of Cav3.2 for treatment of chronic neuropathic pain

In this report, we generated AAV6.2FF-encoded concatemeric 3.2iPA (Co3.2iPA) that combines 3.2iPA1 and 2 as a tandem repeat. We tested its effectiveness via injection of AAV6.2FF-Co3.2iPA into the pathological dorsal root ganglia and evaluated analgesic efficacy in relieving stimulated and spontaneous pain behaviors lasting up to 3.5 months in rat Tibial Nerve Injury (TNI)-induced painful neuropathy. Results showed that AAV6.2FF-Co3.2iPA treatment produced analgesic effects that were comparable between male and female rats in magnitude and time course. Immunohistochemistry and AAV genome analysis confirmed peripheral nerve-restricted AAV6.2FF-Co3.2iPA biodistribution and long-term transgene expression. Inhibition of T-type/CaV3.2 channels and suppression of action potential firing by expressing Co3.2iPA was demonstrated in the human induced pluripotent stem cells-derived sensory neurons (hiPSC-SNs), suggesting a translational potential of sensory neuron-targeted AAV6.2FF-Co3.2iPA treatment for clinical chronic pain conditions that are intractable to currently available pain therapy.