Assessment of Selective Inhibitors of Nuclear Export (SINE) Following Spinal Cord Injury
Abstract
The paralysis and dysfunction that occurs following injury to the spinal cord arises from both the initial primary injury and expansion of the tissue damage that occurs as a result of release of intracellular contents from dead or dying cells, and the controlled and uncontrolled activation of biochemical cascades. Ultimately, the level of disability following spinal cord injury (SCI) is a direct result of the extent of initial tissue damage and the specific cellular responses that determine the balance between tissue damage and wound healing. Preventative measures (e.g., seat belts, armor vehicles, Kevlar vests) have been successful at preventing damage to the spinal cord or decreasing the extent of the primary injury. Unfortunately, once damage has occurred, our ability to prevent its spread has been less successful. Several approaches that block the spread of tissue damage (so-called neuroprotective strategies) are currently in clinical trials for acute SCI (e.g., hypothermia, Riluzole); however, these approaches require rapid administration following SCI (generally before 8 hours after injury), which is often not clinically feasible. Moreover, current approaches do not completely restore function. Development of neuroprotective interventions that robustly protect tissue, block the progression of tissue damage, and have the potential to be administered hours to days post-SCI are desperately needed to reduce disability and to enhance the quality of life of affected individuals. Effective neuroprotective interventions will benefit all newly injured SCI persons. They will be particularly beneficial for the military, as the incidence of SCI relative to regular person is 7 times to 17 times greater than for civilians. This not only impacts the individuals with the SCI (primarily men in their mid-20s, who end up with a life-long disability), but also impacts military readiness and usurps valuable military resources. SCI is a life-altering event. It affects not only the individual but also their families, and it burdens the healthcare system. Identification of clinical-ready compounds, with efficacy in other models of neurological disease, which can be rapidly tested in preclinical SCI models, offers an opportunity to more-rapidly bring a potential therapeutic intervention to humans. The current proposal is a collaboration between Dr. Caitlin Hill, an expert in SCI pre-clinical modeling, and Karyopharm Therapeutics, a clinical-stage pharmaceutical company focused on the discovery, development, and commercialization of drugs targeted at blocking nuclear transport. Karyopharm has developed a series of Selective Inhibitors of Nuclear Export (SINETM compounds), which can be delivered by mouth, are potent and able to reach the spinal cord and are well-tolerated and safe in humans. Unlike previous exportin 1 inhibitors, SINE compounds only transiently bind to exportin 1. This prevents systemic toxicity following administration. SINE compounds inhibit exportin 1, a protein that regulates the exit of ~200 other proteins from the nucleus of cells. These cargo proteins include proteins implicated in apoptosis and necrosis, inflammation, oxidative stress, and axonal degeneration—key cellular processes that are activated following SCI and result in neuroprotection when counteracted. Previous studies by Karyopharm in collaboration with other scientists indicate that verdinexor (KPT-335), the SINE compound that will be tested in the current proposal, substantially promotes locomotor recovery in rats following SCI and effectively enhances function in a pre-clinical model of traumatic brain injury, even when administration is delayed for 3 days. Verdinexor has already undergone rigorous GLP toxicity and pharmacokinetic evaluation in rats and dogs and has proven to be safe in healthy human volunteers in a Phase 1 clinical trial. Thus, verdinexor not only appears to overcome the two main obstacles of current neuroprotective approaches fo
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910179
Entities
People
- Caitlin J Hill
Organizations
- United States Army