Next-generation AAV therapies for management of intractable chronic pain

Chronic pain represents an enormous unmet need (~$635 billion in the US in 2011). The primary treatment for severe chronic pain, opioid administration, causes unacceptable side effects including addiction and fatal respiratory depression while failing to provide therapeutic relief in patients seeking care.1 Without effective alternatives, opioid prescription numbers continue to climb: there were 70,237 prescription-opioid-overdose-related deaths in 2017.2,3 The opioid epidemic highlights the urgent need for new therapeutics to manage chronic pain. Gene therapy, the delivery of genetic material to permanently change gene expression in target cells, could provide long-term pain management with a single dose and is therefore, worthy of investigation. Recombinant adeno-associated virus (rAAV)-delivered gene therapies in particular have shown striking clinical success recently, suggesting a prime opportunity to develop rAAV-based therapeutics for treating chronic pain. We propose to generate a rAAV that specifically targets nociceptors, the neurons that transduce pain, to deliver ligand-gated silencing ion channels that will allow patients to control pain without opioids. Current rAAV engineering approaches lack the cell-type-specificity required to selectively infect nociceptors while sparing non-nociceptor neuronal subtypes however, and off-target silencing of these cells could cause unacceptable toxicity and anesthesia. We developed PESCA, the Paralleled Enhancer Single-Cell Assay, to overcome this limitation and engineer rAAVs that drive unprecedentedly cell-type-specific payload expression. Through PESCA, we aim to create a next-generation therapy that will provide lasting and patient-controlled relief upon administration of a single dose, revolutionizing treatment for the most debilitating and common chronic health condition in the world.