Suprasacral spinal cord injury (SCI) can result in an interruption of descending inhibitory control of the urinary bladder and the urethral sphincters. This results in a condition in which the bladder reacts to filling by contraction rather than relaxation throughout the filling cycle, a condition known as detrusor hyperreflexia. Detrusor hyperreflexia is very often associated with external (striated muscle) and internal (smooth muscle) urethral sphincter dyssynergia, such that the urethral outlet contracts in response to high pressure bladder contractions, rather than relaxing as is normal during a normal voiding. The combined effect of a hyperreflexic bladder contracting against a dyssynergic outlet is frequent high pressure bladder contractions with little or no ability to empty, a condition referred to as neurogenic bladder with detrusor-sphincter dyssynergia (DSD). This condition, if left unchecked, can be life threatening, causing autonomic dysreflexia, ureteral reflux and hydronephrosis/renal failure, and, because of poor emptying providing a safe-harbor reservoir of residual urine for bacterial growth, uncontrolled urinary trac infections and pyelonephritis. The goal of the proposed research is to provide proof of concept for a cell-based therapeutic strategy which will treat the lower urinary tract (LUT) dysfunction following suprasacral SCI with high efficacy while eliminating the side effect/surgical burden associated with the current pharmaceutical, medical device and/or surgical treatments. Briefly, the strategy is to inject cells, which produce the sympathetic neurotransmitters norepinephrine and epinephrine, into the walls of the bladder body. These transmitters are known to quiet bladder body smooth muscle via stimulation of beta-3 adrenergic receptors, and thus reduce the number and force of hyperreflexic bladder contractions. Pharmacological approaches to utilization of beta adrenergic receptors for this therapeutic goal in patients have suffered due to lack of selectivity for the bladder over the cardiovascular (CV) system. Happily, this CV concern may be overcome in the near future by truly beta-3 specific agonists. However, at this time, no beta 3 agonist has been approved by the FDA for use in humans. Regardless, the systemic administration of any pharmacological agent is likely to have side effects and requires daily or more often dosings, making this approach costly over the long term and a risk for patient noncompliance due to systemic side effects, drug costs and inconvenience. Other approaches with local injections or intravesical instillations of neurotoxins appear(ed) promising, but these are also confounded by the need for repeated treatments as the effect of the toxins wear off. The proposed approach has the potential to develop into a single treatment cure for the hyperreflexia seen in SCI patients. Cells from the patient's adrenal medulla may be harvested directly, or other cell types harvested and made to secrete adrenergic catecholamines by molecular biological techniques. The latter is beyond the scope of the initial proof of concept studies outlined in this proposal. In this case, adrenal chromaffin cells will be harvested from normal donor rats and injected into the bladder walls of chronic SCI rats. The ability of the cells to survive in the new environment as well as the efficacy of their catecholamine secretions will be determined physiologically, pharmacologically and histologically first in spinal cord intact animals at 1, 2 and 4 weeks post transplantation. At the optimal time after adrenal chromaffin cell or fat cell transplant, or cell suspension vehicle only injection, as determined by the aforementioned studies in intact animals, chronic SCI rats will undergo cystometric urodynamic evaluation. Following a control period of cystometry in which the efficacy of the cell therapy should be evident in comparison to control animals, the animals will be challenged by pharmacological means to determine the level of beta receptor stimulation. In this way determination of the efficacy of the treatments can be made, as well as the role of adrenergic catecholamines in the response.

Public Health Relevance

Greater than 250,000 Americans are spinal cord injured. 52% of spinal cord injured individuals are considered paraplegic and 47% quadriplegic. Approximately 11,000 new injuries occur each year. Of the more than 250,000 Americans with serious spinal cord injuries and disorders, about 42,000 are Veterans. Thus, any insights into enhancing the general health of SCI patients will greatly impact a large number of veterans as well as soldiers who may be injured in the future. Lower urinary tract (LUT) dysfunction associated with suprasacral SCI can be life threatening at its worst and socially debilitating at its least for these patients. Moreover, SCI patients themselves rank their LUT dysfunctions as primary concerns, even greater than mobility. Successful rehabilitation for the SCI patient must address not only the important health concerns associated with LUT dysfunction, but also the deleterious effects that it has on the patient's quality of life. Additionally, this research would provide proof of concept evidence for the use of cell therapy to treat LUT dysfunction in SCI .

National Institute of Health (NIH)
Veterans Affairs (VA)
Veterans Administration (I21)
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RR&D Translational Program (RRDA)
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Durham VA Medical Center
United States
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