Enhancing Botulinum Neurotoxin Efficacy for Neurogenic Bladder Treatment
Abstract
Spinal cord injury (SCI) has devastating and often lifelong effects on its victims, their caregivers, and Families. Due to the risks associated with military training and service, active-duty military personnel are at significantly higher risk of SCI than individuals in the general population. The most obvious effect of SCI is limb paralysis, which may affect both lower and upper limbs to differing extents. Less obvious, but no less serious, complications include the loss of bladder control. In addition to the emotional distress and diminished quality of life associated with incontinence, bladder dysfunction also puts individuals with SCI at risk of a dangerous secondary condition -- autonomic dysreflexia -- related to, among other things, control of blood pressure. SCI is extremely costly to individuals, both financially and psychologically, and there is currently no cure. The relatively young age at which military personnel are likely to incur their spinal injury, as well as the increased likelihood of surviving their injuries means that such individuals and their families bear a lifelong health and economic burden from their condition. A significant proportion of the clinical expenditures for people with SCI is directly related to management of the urinary tract. Current medications for management of bladder control are often associated with undesirable systemic side effects, and their long-term efficacy is unpredictable and variable. Onabotulinum toxin A (BoNT/A, Botox), which acts by paralyzing overactive muscles, is approved for treatment of complications following SCI, including those affecting the bladder. The availability of Onabotulinum toxin A has greatly improved the care of individuals with SCI. However, the effects are temporary, requiring repeat injections every 6-12 months and long-term data show a significant decline in effectiveness by 7 years for reasons that are not fully understood. As a result, new approaches to improve toxin activity and duration are needed. New findings from our groups have provided important hints into how toxin activity could be improved. Dr. Dong s group has developed different versions of botulinum toxins (BoNTs) that are designed to bind the receptor shown by us to be most relevant in the bladder, a protein called synaptotagmin-1 (Syt1). However, the part of the toxin important for paralyzing overactive muscles is the same as that in BoNT/A currently used to treat bladder complications in individuals with SCI. The activity of these new hybrid toxins is much greater than the activity of BoNT/A, which was tested on bladder tissue from uninjured mice, suggesting that they will also be more active in the setting of SCI. Based on these exciting new findings, we will evaluate several new versions of BoNT for their activity in the bladder following SCI using a variety of complementary techniques to evaluate different aspects of bladder function. Although the proposed studies will focus on an animal model of SCI, we believe the results of our research will be applicable to humans with spinal injury, since the mechanisms that govern bladder function are very similar in both species. Since Onabotulinum toxin A (BoNT/A) is already in clinical use, having undergone critical safety testing, we could expect the novel toxins to move to use in humans relatively quickly, should our proposed studies prove successful. We propose a safe new approach to address a major debilitating consequence of SCI that can be implemented in a straightforward manner. Studies such as this that address a potential new approach to treatment, have the potential to greatly impact the health and quality of life of paralyzed military personnel and their families.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310939
Entities
People
- Rosalyn M Adam
Organizations
- United States Army