Immunological priming potentiates non-viral anti-inflammatory gene therapy treatment of neuropathic pain: Harnessing innate immunity to enhance gene therapy

We recently described a non-viral gene therapy paradigm offering long-term resolution of established neuropathic pain in several animal models. Here, the requirements for long term therapeutic effects are described, and evidence is provided for a mechanism of action based on immunological priming of the intrathecal space. Long-term pain reversal was achieved when two intrathecal injections of various naked plasmid DNA doses were separated by 5 hr to 3 days. We demonstrate that an initial DNA injection, regardless of whether a transgene is included, leads to an accumulation of phagocytic innate immune cells. This accumulation coincides with the time in which subsequent DNA injection efficacy is potentiated. We demonstrate the ability of non-coding DNA to induce short term pain reversal that is dependent on endogenous interleukin-10 (IL-10) signaling. Long term efficacy requires the inclusion of an IL-10(F129S) transgene in the second injection. Blockade of IL-10, via neutralizing antibody, either between the two injections or following the second injection induces therapeutic failure. These results demonstrate that this gene therapy paradigm utilizes an initial “priming” injection of DNA to induce accumulation of phagocytic immune cells, allowing for potentiated efficacy of a subsequent “therapeutic” DNA injection in a time and dose dependent manner.