Testing RNA Aptamers as Analgesic Candidates in a Rat Model of SCI Pain
Abstract
Spinal cord injuries (SCI) are complex neurotraumatic wounds affecting military Service members and Veterans. Neuropathic pain following SCI is a common and serious complication and may last a long time. In fact, at least half of the SCI patients develop chronic pain. SCI-induced pain interferes with daily activities of the patients and significantly impairs their quality of life. SCI-induced pain can also lead to secondary impairment, such as attention deficits and depression. To date, SCI-induced neuropathic pain remains difficult to treat. Only about one-third of patients experience a 50% pain reduction with treatment. Opioids are often prescribed to provide effective pain relief. Yet, there are high risks in misuse, addiction, and overdose of opioids. Therefore, there is a significant, unmet need for developing new therapeutics in order to increase treatment options for patients with SCI neuropathic pain. The proposed research seeks to test a novel class of RNA aptamers for the treatment of SCI pain in an animal model. These RNA aptamers are developed by the Principal Investigator (PI), Dr. Niu’s, laboratory to target a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. Excessive AMPA receptor activities have been implicated in mediating SCI neuropathic pain. Not surprisingly, AMPA receptor antagonists are neuroprotective and are therefore potential antinociceptive agents for treatment of SCI pain but without abuse liability. However, almost all currently available AMPA receptor antagonists are nonselective and poorly water soluble; the potency of these compounds are also generally low. Consequently, the therapeutic potential of targeting AMPA receptors to treat neuropathic pain resulting from SCI and other types of chronic pain has not been fully explored. Different from small-molecule compounds, RNA aptamers are a new class of AMPA receptor antagonists and have better pharmacological properties. Our aptamers have higher potency and higher selectivity than traditional small-molecule compounds. Because aptamers are RNA molecules, they are water soluble by nature. As a group of biological agents used as potential drugs, they are stable in vivo by our design and are not expected to be immunogenic and toxic. These properties would allow us to more tightly and selectively target and control AMPA receptor activities for pain control with minimal or no side effects. In addition, RNA aptamers will be readily delivered using intrathecal injection to the spinal column, a routine pain medication delivery approach. To explore the therapeutic utility of our aptamers, we propose to use a clip-compression SCI model in rats. The main advantages of this compression model are: the etiology of compression injury reflects clinically observed spinal cord trauma, and the model provides a robust, long-term stable and reproducible SCI pain symptomology, particularly for below-level pain responses. The short-term goal of our study, designed to complete in 2 years, is to test the efficacy and safety of AMPA receptor RNA aptamers in this rat model of SCI neuropathic pain. If successful, we will identify some of the aptamers for clinical trials as the next step. The ultimate goal of our research is to produce a new RNA-based drug for an effective treatment of SCI pain. Therefore, the outcome of our research is expected to contribute to improving the function, wellness, and overall quality of life for military Service members as well as their caregivers, families, and the public.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010385
Entities
People
- Li Niu
Organizations
- State University of New York at Albany
- United States Army