Enhancing Recovery of SCI-Induced Bladder Dysfunction Using Small Molecules
Abstract
Spinal cord injury (SCI) affects more than 250,000 Americans, with the majority of SCI individuals being paraplegic and 47% quadriplegic. Approximately 11,000 new injuries occur each year. Of the total number of Americans with SCI, nearly one-fifth are ex-military personnel. SCI is an extremely debilitating condition, affecting not only the mobility of an individual but also impairing the function of various internal organs. Chronic SCI-induced loss of urinary bladder control can be life threatening at its worst (urinary tract infections [UTIs] and potential kidney damage) and at a minimum, socially debilitating. Chronic SCI patients themselves rank their loss of urinary bladder control as a primary concern, even greater than mobility. The degree of impairment to bladder control depends on whether there is complete (spinal cord transection [SCT]) or incomplete (spinal cord contusion [SCC]) injury. Accordingly, SCI symptoms can range from neurogenic detrusor overactivity (NDO) and urine leakage (incontinence) to detrusor-sphincter-dyssynergia (DSD) and the inability to initiate urination, requiring self-catheterization to empty the bladder. There are currently only a few available treatments for bladder overactivity and none for the more serious DSD. Thus, the development of new drugs to improve the DSD and NDO of SCI patients will greatly impact a large number of military veterans as well as soldiers who may be injured in the future. Applicability of the research, target SCI patient population and potential clinical outcomes: The proposed development and animal validation stage work will help develop LM11A-31, an orally administrable small molecule drug that targets the p75 neurotrophin receptor in the bladder and spinal cord to treat SCI-induced loss of bladder control. The p75 neurotrophin receptor has been shown to be involved in various neurodegenerative conditions, and our preliminary data indicate that it is also involved in-bladder complications resulting from SCI. LM11A-31 prevents activation of degenerative signaling while promoting nerve regeneration pathways. Preliminary findings demonstrate that daily oral administration of LM11A-31 is the first agent that treats both NDO and DSD in mouse models. These effects could be translated in SCI patients to decrease NDO, incontinence, catheterization, UTIs, DSD, and kidney damage to improve the health and quality of life of SCI patients. Accordingly, we propose to study the therapeutic benefit of LM11A-31 in male and female SCT and SCC mice assessed using a range of physiological and molecular techniques. Both SCT and SCC injuries will be evaluated, as the pathological outcomes can vary significantly depending upon the extent of injury. Our preliminary data demonstrate the efficacy of LM11A-31 treatment in complete SCI, and we hypothesize that there will be even more beneficial effects in SCC-induced bladder dysfunction. Projected time to achieve person-related outcome: These findings are applicable to all patients that experience bladder control problems resulting from complete or incomplete SCI and represent a novel treatment option to treat NDO, DSD, and their complication. LM11A-31 is currently in Phase II clinical trials for treating Alzheimer s disease and has passed the initial Phase I safety criteria. Thus, this agent can readily be translated to clinical trials in SCI patients.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810436
Entities
People
- Anthony J Kanai
Organizations
- United States Army
- University of Pittsburgh