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A first target indication: 

neurogenic bladder

The lower urinary tract (LUT) is extensively innervated to allow for voluntary and involuntary control of urine storage and evacuation. Spinal cord injuries (SCI) seriously compromise the nervous system and often lead to neurogenic LUT dysfunctions including neurogenic bladder, a condition that significantly impacts a patient’s quality of life and a source of multiple complications that lead to morbidity and mortality.
 

A heavy patient burden with significant economic cost

 

Depending on the location of the SCI, different patterns of neurogenic bladder are observed. If the lesion occurs between the brainstem and the sacrum (above segments L1-L2 of the spinal cord), patients display neurogenic detrusor overactivity, or NDO: the bladder sensory neurons trigger an abnormal reflex that causes uncontrolled contractions of the detrusor (the muscle that lines the bladder), leading to varying degrees of incontinence. In addition, simultaneous contractions of the urethral sphincter, or its inability to relax, lead to urine retention, urinary tract infections (UTIs) and an increased pressure within the bladder that causes renal failure in the long run.

 

As many as 85% of individuals with a traumatic SCI, display a suprasacral lesion and present an NDO, with an absolute prevalence of 425K in the developed world [Hamid, R. t al.]. NDO is responsible for chronic UTIs whose complications are a major reason for rehospitalization [ Paker, N. et al. | DeJong, G et al. ] the main cause of mortality in SCI patients in developing countries [WHO International perspectives on spinal cordinjury; 2013], and a real economic burden on healthcare systems [White, B. A. B. et al.].

Current therapies: short-term strategies that fail to prevent complications

 

Treatments for NDO patients aim to block uninhibited detrusor contractions and to decrease bladder pressure thus preventing urological complications. Several pharmacological and surgical options are currently available that display various efficacy and safety profiles. However, none of these options successfully addresses the need to both prevent abnormal contractions of the bladder and preserve the motoneuron function to allow for normal micturition patterns. As a result, these treatments are most often associated with intermittent self-catheterization (ISC), an efficient method for bladder emptying that is associated with a high risk of UTIs.

 

An HSV-1-based gene therapy for the long-term management of NDO

 

To overcome the limitations of currently available treatments, EG 427 has developed an HSV-1 vector for the delivery and expression of a transgene encoding the light chain of botulinum toxin F, BoNT-F LC, specifically in sensory neurons [Joussain, C. et al.]. This gene therapy strategy achieves long-lasting BoNT-F LC expression to block neurotransmission through sensory neurons, but spares motors neurons, preserving the ability of the bladder to contract in view of restoring micturition.  

 

In vivo preclinical studies in animal models have demonstrated the ability of an HSV-1- expressed transgenic BoNT-F LC to block sensory neurons and to relieve SCI-associated NDO. While further preclinical research is under way, a first-in-man phase I/II study should start by the end of 2022.

HSV-1-based gene therapy to treat neurogenic bladder
after spinal cord injury

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What Our scientific founder says

Our strategy fulfills a double objective in the management of neurogenic detrusor overactivity, which affects many patients who have suffered a spinal cord injury: it provides a real medical benefit by preventing complications such as recurrent urinary tract infections and renal failure, but also represents a major improvement to the quality of life of patients by restoring continence.

Pierre Denys, MD, PhD,

International expert in neuro-urology