UMIP-145 – Long Acting Local Analgesic

Problem: Persistent pain costs about $650 billion annually in health care costs and lost productivity. A National Health Interview Survey conducted in 2012 estimated that nearly 50 million American adults suffer from significant chronic pain or severe pain. Other studies suggest the burden of pain is higher. Currently available treatments for chronic pain are associated with disadvantages that leave most patients inadequately treated. Current local anesthetics, for example, are short acting and disabling due to complete sensory and motor blockade. Opioid drugs, including morphine, are the primary treatment for, e.g., post-operative and chronic pain conditions. Long-term opioid use in treating chronic, non-cancer pain has increased dramatically over the past few decades, and opioid abuse, tolerance and dependence are major public health concerns. Indeed, side-effects of opioid administration (e.g., tolerance, drug dependence / addiction, respiration depression, constipation, nausea, pruritis, sedation, and mood swings), limit opioids’ therapeutic potential, and the absence of suitable alternatives has led to an epidemic of opioid overuse, abuse, and life-threatening complications. In the United States prescription opioid abuse costs alone were estimated at about $55.7 billion in 2007. Almost half this cost was attributed to workplace costs (e.g., lost productivity), 45% to healthcare costs (e.g., abuse treatment), and 9% to criminal justice costs. Despite a considerable amount of research into pain medications, there remains a need for therapeutic options that provide analgesia while minimizing (or avoiding) the adverse effects associated with opioid use. Technology: Researchers at the University of Miami have developed novel methods of treating and preventing chronic pain through the administration of viral expression vector comprising a nucleic acid sequence encoding carbonic anhydrase 8 (fragment)(CA8), 10 (CA10) or 11 (CA11). The long-term expression from nerve blocks or intra-articular injection of CA8, CA10 or CA11 results in the suppression of pain through sensory neuron quieting, providing the patient with long-term pain relief. References: • Upadhyay U, et al., Reversion mutation of cDNA CA8-204 minigene construct produces a truncated functional peptide that regulates calcium release in vitro and produces profound analgesia in vivo. Mammalian Genome, in press 2020. • Upadhyay U, et al., Profound analgesia is associated with a truncated peptide resulting from tissue specific alternative splicing of DRG CA8-204 regulated by an exon-level cis-eQTL. PLoS Genet. 2019 Jun 14;15(6). PMID: 31199789. • Gerald GZ. et al., Human Carbonic Anhydrase-8 AAV8 Gene Therapy Inhibits Nerve Growth Factor Signaling Producing Prolonged Analgesia and Anti-Hyperalgesia in Mice. Gene Ther. 2018 Jul;25(4):297-311 PMCID: PMC6063772. • Fu ES, et al., Impact of human CA8 on thermal antinociception in relation to morphine equivalence in mice. Neuroreport. 2017 Dec 13;28(18):1215-1220. PMCID: PMC5685868. • RC Levitt, et al., Car8 dorsal root ganglion expression and genetic regulation of analgesic responses are associated with a cis-eQTL in mice. Mammalian Genome, May 25, 2017. PMID: 28547032. • Zhuang GZ, et al., Carbonic anhydrase-8 regulates inflammatory pain by inhibiting the ITPR1-cytosolic free calcium pathway. PLoS One. 2015 Mar 3;10(3):e0118273. Peter Gutenberg pxg372@miami.edu 305-243-4604