Recombinant dimeric PDZ protein inhibitors for long-term relief of chronic pain by AAV therapeutics

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 and addiction liability. The inadequate state of current treatment, the chronic nature of particularly neuropathic pain, and the high impact on quality of life render 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 viral (AAV) vectors. This strategy prevents mechanical allodynia in mouse inflammatory and neuropathic pain models and reverses neuropathic pain in advanced stages for an entire year. Pain relief was obtained by selective targeting of several relays along the somatosensory pain pathways without observed side effects. Importantly, full pain relief was also achieved by selective transduction of peripheral neurons, which is highly attractive for therapeutic intervention since it is less likely to cause intolerable side effects. ### Competing Interest Statement The recombinant dimeric peptides, their usage, and their extended utilization are disclosed in two patent applications currently being processed at the European Patent office (EPO) and the United States Patent and Trademark Office (USPTO). KLM and ATS have ownership interest and are co-founders of Zyneyro, a company having exclusive license rights on the two patents, which are owned by the University of Copenhagen, Denmark. All other authors have no competing interest to declare.