Afferent Neuron Viral Vectors for Neurogenic Detrusor Control
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Solution Overview
Problem
Current treatments for neurogenic detrusor overactivity (NDO), such as botulinum neurotoxin injections and surgical deafferentation, suffer from adverse effects, toxin diffusion, and loss of pelvic sensation, while existing viral vectors lack specificity and stability for afferent neuron modulation.
Innovation Solution
A gene therapy approach using a viral expression vector with a transcription cassette that selectively silences or inhibits neurotransmission in bladder afferent neurons, utilizing afferent neuron-specific promoters and long-term expression sequences to achieve stable transgene expression.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If botulinum neurotoxin injections are used to treat NDO, then involuntary detrusor contractions are reduced, but toxin diffusion occurs and pelvic sensation is lost
Solution Approach 1:
The patent uses afferent neuron-specific promoters (such as TRPV1 promoter, CGRP promoter, or Substance P promoter) to drive transgene expression selectively in bladder afferent neurons. This ensures that the therapeutic effect is localized to the target neuron population while preserving function in other neurons, thereby achieving local quality control that prevents toxin diffusion effects and preserves pelvic sensation.
2Reliability
If surgical deafferentation is performed to treat NDO, then involuntary detrusor contractions are reduced, but pelvic sensation is lost
Solution Approach 1:
The patent segments the nervous system into efferent and afferent components and selectively targets only the afferent pathway using neuron-specific promoters. This segmentation allows silencing of bladder afferent neurons to reduce involuntary contractions while leaving efferent neurons and other sensory pathways intact, thereby preserving pelvic sensation unlike complete surgical deafferentation.
Solution Approach 2:
The patent uses viral vectors as intermediaries to deliver silencing constructs (such as shRNA or antisense RNA) specifically to afferent neurons. This intermediary approach allows selective modulation of afferent signaling without direct surgical intervention, preserving sensation while achieving therapeutic effect.
3Ease of manufacture
If existing viral vectors are used for afferent neuron modulation, then gene delivery is achieved, but specificity and stability are insufficient
Solution Approach 1:
The patent changes the promoter parameter from general or non-specific promoters to afferent neuron-specific promoters (TRPV1, CGRP, Substance P promoters). This parameter change ensures that transgene expression is restricted to afferent neurons, achieving the required specificity and stability for therapeutic effect without off-target effects.
Data Source
AI summary
The present invention provides a method and a pharmaceutical composition for the treatment of the NDO comprising the viral expression vector carrying a transcription cassette that harbors transgene(s) inhibiting/silencing neurotransmission or synaptic transmission of afferent neurons.