Viral Vector Silencing of Bladder Afferent Neurons in NDO
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Solution Overview
Problem
Current treatments for neurogenic detrusor overactivity (NDO), such as botulinum neurotoxin injections and surgical deafferentation, suffer from toxicity, diffusion issues, and irreversible sensory loss, necessitating a more selective and stable gene therapy approach to target abnormal spinal reflexes without affecting other neurons.
Innovation Solution
A viral expression vector is developed to deliver transgenes that inhibit synaptic transmission in bladder afferent neurons, using afferent neuron-specific promoters and long-term expression sequences, such as AAV and HSV vectors, to selectively silence neurotransmission and maintain bladder function.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If botulinum neurotoxin injections are used to treat NDO, then involuntary bladder contractions are reduced, but the treatment suffers from diffusion issues and toxicity
Solution Approach 1:
The treatment is segmented by using a viral vector system that specifically targets afferent neurons, separating the therapeutic effect from non-specific diffusion. The vector delivers silencing sequences only to the intended neuronal population, preventing widespread toxicity while maintaining localized effectiveness in reducing involuntary contractions.
Solution Approach 2:
A viral vector serves as an intermediary carrier to deliver the silencing sequences to afferent neurons. This intermediary approach replaces direct toxin injection with a controlled delivery system that targets specific neurons through viral tropism, reducing off-target effects and toxicity while maintaining therapeutic efficacy.
2Reliability
If surgical deafferentation is performed to treat NDO, then abnormal spinal reflexes are eliminated, but irreversible sensory loss occurs
Solution Approach 1:
The harmful overactive reflex component is extracted and silenced selectively through gene therapy, while preserving the normal sensory function. The silencing sequences specifically target the pathological afferent signaling without removing the entire sensory pathway, eliminating abnormal reflexes while maintaining necessary sensory input for bladder function.
Solution Approach 2:
The approach changes the functional parameter of afferent neurons from overactive to silenced state through reversible gene expression, rather than permanently removing the neurons. This parameter change achieves reflex control while preserving the neuronal structure and potential for future reversal if needed.
3Reliability
If non-selective nerve blocking is performed to treat NDO, then detrusor overactivity is reduced, but other neuron functions are affected
Solution Approach 1:
The treatment applies local quality by making the silencing effect specific to afferent neurons only, differentiating them from efferent neurons. The viral vector and silencing sequences are designed to target afferent neuronal characteristics, creating a localized therapeutic effect that spares other neuronal populations and their functions.
Solution Approach 2:
The system incorporates feedback through promoter elements that respond to afferent neuron-specific markers, ensuring selective silencing. The viral vector expression and silencing sequence activation are regulated by feedback mechanisms that recognize afferent neuronal identity, maintaining selectivity while achieving overactivity reduction.
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.