Recombinant dimeric PICK1 peptide inhibitors for long-term relief of chronic pain by AAV therapeutics.

Chronic neuropathic pain's impact, persistence, and limited treatments render it relevant for gene therapy. Here, we describe the development and application of self-assembling dimeric peptide inhibitors of the pain-associated scaffolding protein PICK1 (protein interacting with C-kinase 1), delivered by adeno-associated viral (AAV) vectors. In mice, these peptides prevent mechanical allodynia in inflammatory and neuropathic pain models and reverse neuropathic pain for up to 1 year. Targeting somatosensory pathways relieves pain without overt side effects, while selective transduction of dorsal root ganglion (DRG) neurons is sufficient to provide pain relief. Using proteomic and phosphoproteomic analysis of DRG tissue, we identify regulation of protein kinase C alpha (PRKCA) as a candidate that potentially shapes this pain-relieving phenotype. We finally confirm PICK1 expression and peptide target engagement in human donor tissue, supporting the potential of AAV-encoded PICK1 inhibitors as a clinically meaningful strategy for neuropathic pain conditions.