Recombinant GABAergic Cells as a Therapy for Chronic Neuropathic Pain
Abstract
Topic: The project addresses Fiscal Year 2018 Peer Reviewed Medical Research Program Topic Areas “Chronic Pain Management” and “Non-Opioid Pain Management.” Overview: Chronic pain is a debilitating condition with 3 million cases each year in the U.S. A recent national survey estimated over 65% Veterans reported chronic pain, with almost 10% with severe pain. The chronic pain can result from the injury or disease and persist for months to years beyond the initial injury, significantly impacting daily activities of patients, their family members and caregivers. As the Veteran populations are exposed to injuries involving damage of the peripheral or central nerves at a higher rate than the civilian population, chronic neuropathic pain is one of the major chronic pain phenotypes in Veterans. Although the etiology of neuropathic pain may vary, there are some overlapping mechanisms described in various neuropathic pain models. One of the key events underlying development of chronic pain is reduced inhibition in the spinal cord, causing misinterpretation of the incoming signal from the periphery. Signals may be miscoded as “painful” even in the absence of any painful stimuli due to overexcitation of the spinal neurons. Dysfunctional signaling of GABA as an inhibitory neurotransmitter is suggested as the major cause of neuronal hyperexcitability. Pharmacological targeting of GABA receptors is insufficient to rebalance the spinal signaling due to widespread location of GABAergic receptor throughout the central nervous system. Targeted approaches are therefore investigated. Transplantation of GABAergic cells showed reduction of chronic pain and partial restoring of the inhibitory balance in the spinal cord. However, the beneficial effect of this approach has been observed only for a limited time in the animal models, and more research is needed to evaluate its potential in clinical setting. To improve the analgesic outcome of this approach, cells may be engineered to produce additional analgesic peptides. The benefits of using recombinant cells are that it allows targeting multiple pain-processing pathways, to rebalance inhibitory signaling and to replace dysfunctional neurons at the same time. In this proposal, as a recombinant peptide produced by GABAergic cells, conotoxin MVIIA will be investigated. The conotoxin is a Food and Drug Administration-approved therapeutic peptide for the treatment of chronic neuropathic pain. However, due to its poor penetration through the blood-brain barrier, it has to be delivered via intrathecal catheters. Although it is an efficient way to deliver a drug in a somewhat targeted way, there are several risk factors associated with catheters, such as inflammation and misplacement, as well as the overall cost of the procedure reaching up to $30,000 per year. Critical Problem: Currently there is no effective treatment for long-term alleviation of chronic pain. Opioids, as the most potent analgesics, are often used in chronic pain management; however, their prolonged use is associated with development of tolerance and addiction, and becoming a modern epidemic in the U.S. Therefore, there is an urgent need to develop novel treatment approaches for chronic pain. Innovation: Targeted delivery of analgesic substances via cell-based therapy may overcome the issue of systemic side effects and help to restore dysfunctional pain signaling in the spinal cord. This proposal will investigate the potential of cell-based delivery of recombinant MVIIA as a single procedure that may be combined with other surgical interventions, thus reducing exposure of patients to multiple surgeries. Targeted delivery of MVIIA in combination with GABAergic cell may enhance the overall analgesic effect of the approach. Impact: This suggested approach or a modified version with direct viral delivery of recombinant genes may be used to target other chronic pain syndromes in Veterans and improve the qua
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910042
Entities
People
- Stanislava Jergová
Organizations
- United States Army
- University of Miami