Accelerating Translation of a Small-Molecule KCC2 Enhancer to Promote Recovery and Reduce Neuropathic Pain After SCI Using a Pig Model
Abstract
Objectives and Rationale: The overarching goal of this application is to evaluate the efficacy of a new oral drug for restoring movement, reducing spasticity, and alleviating neuropathic pain after spinal cord injury (SCI) in a highly translational and clinically-relevant large animal model. We posit that our new therapeutic will harness neuroplasticity and maximize the function of spared, but dormant, neural connections to improve function after SCI. Our scientific rational for this therapeutic is based on the fact that the majority of SCI patients are incompletely paralyzed (i.e., functionally incomplete). Even completely paralyzed (i.e., functionally complete) patients possess spared neural connection spanning across and around the injury site. This indicates that motor deficits are often much greater than anatomical damage. A drug with ability to reactivate this spared, but dormant, spinal cord tissue could substantially improve function after SCI. After SCI, there is a local downregulation of the CNS-specific potassium/chloride co-transporter, KCC2, which leads to excitation/inhibition imbalance. Without KCC2, spared neurons no longer function properly. Treatments that enhance KCC2 restore function in rodent SCI models. Our data and other research in rodents show that KCC2 enhancements reduces both pain and spasticity. Potential Clinical Applications and Benefits: There are currently no drugs or therapeutics on the market that enhance KCC2 function. Importantly, our therapeutic KCC2 enhancement strategy can be used in sub-acute and chronic timelines after SCI and in both tetraplegia and paraplegia. Thus, nearly all patients with SCI could be treated with this therapeutic approach. If successful, this research would be well suited for rapid translation and could in short-order affect clinical practice for the treatment of SCI. The pig is an excellent preclinical model for human SCI due to the many similarities between pigs and human. For example, pigs match the size and weight of humans over a wide range of developmental stages. The pig nervous system is nearly the same size as that of the human, has similar blood flow, has similar gray and white matter ratios. We have shown that the anatomy and function of the pig spinal cord resembles human more than rodent. The immune responses in pigs are very human-like, much more so than immune responses in rodents. Additionally, our team has back- translated (from the clinic to the pig) outcome measures to evaluate motor and sensory function (e.g., neuropathic pain) after SCI that are used in human medicine. Upon completion of these experiments, we will have determined if our novel KCC2 enhancement therapeutic can restore function, reduce neuropathic pain, and reduce spasticity in highly clinically-relevant, non-rodent animal model. This study will support an Investigational New Drug (IND) application to the U.S. Food and Drug Administration (FDA), the next step in translating this new therapeutic approach to clinical trials. Thus, the work proposed herein could lead to a first- in-class KCC2 therapy for both acute and chronic SCI patients to treat paralysis, pain and spasticity. Such a drug could also be used in combination with neuroprotective treatments. Projected Timeline: The typical path for development of a new therapeutic involves basic research to develop the idea and to test proof-of-concept. Data from the FDA indicates that this phase often lasts up to 25 years. We have nearly completed this phase for our novel KCC2 inhibitors and have demonstrated proof-of-concept in several rodent models. The next stage is preclinical testing including testing in large animal models that support an IND-application. We have done some preclinical safety and dose testing, and the research we propose here will provide effectiveness testing of our new therapeutic in a clinically-relevant large animal model. During the 3 years of this project, we will ac
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210923
Entities
People
- Joanna Stanicka
Organizations
- United States Army