Gith Noes-Holt

Madsen Lab

Development and investigation of AAV gene therapies and peptide inhibitors treating chronic pain

Abstract: Chronic pain is estimated to affect 20% of the adult population, and the burden on individual patients and society caused by chronic pain is escalating. Current treatments, including opioids, anti-convulsants and
anti-depressants are only moderately effective and limited by severe side-effects as well as addiction liability. The inadequate state of current treatment together with the chronic nature of particular neuropathic pain and the high impact on quality-of-life renders chronic pain conditions relevant for gene therapy. Here, we describe the development of a self-assembling, bivalent peptide inhibitor of the pain associated scaffold protein PICK1, delivered by adeno associated virus. This strategy enables prevention of mechanical hyperalgesia in inflammatory as well as neuropathic pain models in mice, and can reverse neuropathic pain in advanced stages for a full year. Pain relief was seen by selective targeting of several relays along the somatosensory pain pathways without observed side-effects. Importantly, full pain relief was achieved also by selective transduction of peripheral neurons, which is highly attractive for therapeutic intervention since it is less likely to cause intolerable side-effects.