Developing Gene Therapies Targeting Cannabinoid Receptors for Treatment of Chronic SCI Pain
Abstract
Neuropathic pain resulting from injury or diseases affecting the nervous system often persists and may escalate over time. Many patients with spinal cord injury (SCI) develop chronic neuropathic pain, the severity of which, in some cases, may supersede other concerns and greatly reduce overall quality of life. The presence of untreated pain can interfere with rehabilitative strategies, thus reducing potential gains in functional recovery. Pain following SCI is particularly challenging, as conventional analgesics are marginally effective at best, and often fraught with untoward side effects. Cannabinoids are a promising and potent class of agents in the management of pain, and preclinical studies in rodent models suggest that cannabinoids may be particularly potent in relieving neuropathic pain. Anecdotal clinical reports and patient surveys suggest that cannabinoid receptor activation with ligands derived from Cannabis sativa reduces neuropathic pain. Despite the potential benefits and value of cannabinoids, clinical acceptance has been limited due to CNS side effects at systemic analgesic doses and the fear of abuse potential. The goal of the proposed studies is to overcome clinical barriers to effective utilization of this promising therapeutic target for intractable pain by identifying and developing potent local delivery approaches using cannabinoid peptides. Marine cone snails produce a wealth of diverse and selective peptides (conopeptides) and have become a major focus for new drug development in the treatment of central nervous system (CNS) injury and disease. In particular, a significant number of these conopeptides are promising therapeutics for pain. Interestingly, many cone snail target prey are known to express cannabinoid (CB1 and CB2) receptors; thus, it is likely that cone snails produce cannabinoid agonists. Using cone snail venom extracts, preliminary screening in pain models in our laboratory has identified several potential candidates that can be characterized and developed into novel therapeutics for the treatment of pain. Since these are peptidergic, long-term local spinal delivery may also be achievable via gene therapy, thereby avoiding widespread side effects. The specific aims of this proposal are: (1) To identify and characterize potential analgesic cannabinoid conopeptides acting as cannabinoid agonists at CB1 or CB2 receptors. To accomplish this, cone snail venom components with cannabinoid agonist activity will be identified using in vitro and in vivo assays and serial sub-fractionation to select promising conopeptides. (2) To evaluate cannabinoid conopeptide therapeutic efficacy by chronic intrathecal infusion in an SCI neuropathic pain model. Rats will be tested for neuropathic pain reduction using a battery of behavioral tests for allodynia, hyperalgesia, and spontaneous pain. Possible locomotor and physiological side effects will also be assessed. The most promising (most potent pain reduction with limited side effects) will be carried forward for further evaluation and development. (3) To develop cannabinoid conopeptide gene therapy strategies for long-term alleviation of neuropathic pain. cDNAs will be generated from selected conopeptides and clinically acceptable viral vector delivery systems will be developed for sustained delivery of analgesic peptides to pain modulatory regions. Sustained conopeptide transgene expression and pain alleviation will be evaluated using behavioral, pharmacologic, neurochemical, and histochemical outcome measures and monitored for side effects. If successful, this project should overcome barriers in harnessing the promising analgesic potential of the cannabinoid system in the therapeutic management of debilitating chronic SCI pain.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810715
Entities
People
- Jacqueline Sagen
Organizations
- United States Army
- University of Miami