Anti-NGF Local Therapy for Autonomic Dysreflexia in Spinal Cord Injury

Abstract

Abstract : Autonomic dysreflexia (AD), which induces excessive elevation of blood pressure, is a potentially life-threatening medical emergency that occurs in persons with spinal cord injury (SCI) at or above the mid-thoracic spinal cord segment. Since the most common source of stimulation that initiates AD is the genitourinary tract including bladder distention, followed by colorectal distension, elimination of activation of bladder sensory pathways during bladder distention could significantly reduce the incidence and/or degree of AD in SCI. Because previous studies have indicated that increased levels of nerve growth factor (NGF) in sensory pathways are one of the key factors to induce increased excitability of sensory pathways after SCI, anti-NGF therapy could be an attractive treatment of AD in SCI patients. However, systemic anti-NGF treatment such as the use of NGF antibodies reportedly induces some side effects. Therefore, we hypothesize that the local therapy of NGF antisense delivery using liposomes (LPs) in the bladder could reduce the activation of bladder sensory pathways, thereby suppressing AD during bladder distention after SCI. Using adult female rats with chronic spinal cord injury induced by Th4 spinal cord transection, we will investigate: (1) the contribution of hyperexcitable bladder sensory pathways in the emergence of AD in SCI (Aim 1), and (2) the effects of intravesical delivery of NGF antisense-liposome conjugate, which reduce NGF expression in the bladder, on AD in SCI (Aim 2). If successfully completed, this study directly addresses the feasibility of local NGF antisense treatment for SCI-induced AD and provides the foundation for future clinical translation of local NGF antisense therapy in military service members, their family members, and/or the U.S. veteran population, who suffer from autonomic dysreflexia due to SCI.