Adeno-Associated Virus (AAV) gene therapy has the potential?as yet unrealized?to provide targeted anal- gesic agent delivery in pain patients, if optimized vectors can achieve a key objective in large animals: efficient and anatomically selective gene delivery to the neurons of a dorsal root ganglion (DRG). Such gene targeting could turn even opioids (gene-encoded) into a safe and non-addictive treatment of chronic locoregional pain. Pain is a national health problem affecting 116M Americans at a cost of $560B/year. Untargeted opioids used to treat pain such as oral oxycodone act on multiple neural structures other than the DRG causing side effects such as respiratory arrest (via the brainstem), hallucinations (via the cortex), and addiction (via the mesolimbic system). 18,893 Americans died from prescription opioids in 2014 and 1.9 million were addicted to them. Key technologies required for AAV gene therapy of pain already exist such as multiple therapeutic genes and a clear definition of a target cell population, DRG neurons. In fact, analgesic efficacy of DRG-directed AAV gene vectors has been thoroughly proven in rodent models. Astonishingly, however, large animal testing has not been reported for any analgesic gene vector, neither AAV nor any other vector type. Hypothesis: Anatomically selective delivery of AAV vectors encoding a known analgesic gene to select DRG can reverse pain-related behavior in a large animal model of a clinically common loco-regional pain syndrome.
Aim 1. Optimize AAV vector design by high-throughput testing of strains in vivo in DRG of swine. A critical bottleneck in vector optimization is comparative testing of multiple strains in vivo. We will use the newly developed high throughput RNA-and-DNA ?Barcode? sequencing methodology developed by the Co-I that allows concurrent quantification of transduction efficiency and transgene expression of up to hundreds of AAV strains in a single experiment to define the optimal vector characteristics for DRG neuron targeting.
Aim 2. Develop Magnetic Resonance Imaging (MRI)-guided vector targeting to DRG in swine. MRI imaging of the swine spine showed superior demarcation of DRG compared with CT. MRI- mislocalization artifacts of needles used could be corrected in phantom models. We will develop MRI-guided AAV targeting of DRG by convection enhanced delivery while integrated toxicological endpoints into the aim.
Aim 3. Test the analgesic efficacy of AAV in a model of chronic knee osteoarthritis (OA) pain in swine. Knee OA ranks amongst the two most common causes of chronic pain in humans. We established a model of chronic knee (?stifle?) OA in swine. We will use the model to test the analgesic efficacy and integrated toxicity endpoint of AAV expressing opioid genes in the DRG . Impact: Large animal gene transfer optimization and efficacy testing performed along with an assessment of toxicological endpoints will advance the concept of targeted analgesic AAV gene therapy of DRG to the point where a pre-IND discussion can be initiated and the additional investment in formal toxicology testing justified.

Public Health Relevance

Chronic pain affects 116 million Americans. The total financial costs of this epidemic are >$560 billion (as stated in PA-16-188). Conventional treatments use a variety of drug regimens but frequently fail to control pain. Targeted gene therapy is an important goal, because it addresses a public health crisis caused by the effects of untargeted, ?systemic? delivery of opioids such as oxycontin acting on the brain. These drugs cause respiratory arrest, hallucinations, and addiction. 18,893 Americans died from prescription opioids in 2014 and 1.9 million were addicted to them; 10,574 died from heroin and 586,000 were users, most of whom were first addicted to prescription opioids. Recent studies in have demonstrated that chronic pain can be controlled by gene therapy, i.e. delivering a therapeutic gene into the cells responsible for pain signaling. These cells are found in small structures located adjacent to the spinal cord called dorsal root ganglia (DRG). The goal of this study is to develop a technique to deliver a gene therapy vector to DRG using clinical computed tomography and MRI technology. The research proposed in this application will allow us to determine the most viable treatment approach for future development for human use with a special focus on severe pain from advanced cancer and severe osteoarthritis.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Gene and Drug Delivery Systems Study Section (GDD)
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Oshinsky, Michael L
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Interventional Analgesix, Inc.
United States
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