Emergence of a spinal micturition reflex after SCI: abolition by silencing of hyper-excited C-fiber bladder afferents by gene therapy to restore continence and micturition
Spinal cord injury (SCI) causes neurogenic detrusor overactivity (NDO), a severe disabling disorder characterized by involuntary detrusor contractions during bladder-filling phase. SCI NDO is due to the emergence of a spinal reflex, mediated by hyper-excited C-type bladder afferents, responsible for urinary incontinence and renal failure. NDO treatments, oral antimuscarinics or botulinum toxin (BoNT) intradetrusor delivery, inhibit bladder contractions by blocking efferent motor outputs to the bladder. Consequently, neural control of micturition is impaired and intermittent bladder catheterization is mandatory for voiding. We are designing a gene therapy approach to perform selective and long-lasting molecular bladder deafferentation to treat NDO. Herpes simplex virus (HSV-1)-based vectors will be used to express in bladder afferents BoNT light chains (LC) driven by long-term afferent neuron-selective promoters. BoNT LC are safe peptides cleaving SNARE proteins, thus abolishing neurotransmitter release and disrupting bladder afferent synaptic transmission. Vectors will be designed, assessed and selected in vitro and in vivo in a NDO rat model. Ultimately this bladder neurosurgical deafferentation will treat NDO while sparing motor bladder outputs. The efferent limb of the spinal reflex will thus remain eligible for on demand electrical stimulation to elicit micturition. This will lead to restoration of continence and micturition without bladder catheterization.
gene therapy, Spinal cord injury, Neurogenic detrusor overactivy (NDO), viral vectors
2017 - 2021
François Giuliano (Coordinator)