Downmodulating DeltaNp63 to Activate Dormant Olfactory Stem Cells
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Solution Overview
Problem
Adult stem cells in the olfactory epithelium, specifically horizontal basal cells, become dormant and lose their multipotency with age, leading to olfactory disorders such as anosmia and hyposmia, as they fail to activate and replenish olfactory sensory neurons.
Innovation Solution
Reducing the level of ΔNp63 in dormant epithelial stem cells, particularly horizontal basal cells, using agents like microRNA 203, to activate them into a multipotent state, allowing them to differentiate into neuronal and non-neuronal cell types and repopulate the olfactory epithelium.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If ΔNp63 levels are maintained in dormant horizontal basal cells, then the cells remain in a quiescent state, but they lose multipotency and fail to regenerate olfactory sensory neurons
Solution Approach 1:
The patent changes the biochemical parameter of ΔNp63 protein levels in HBCs by administering agents that downmodulate ΔNp63. This parameter change triggers the transition from quiescent to activated state, enabling multipotency and neurogenic capacity while maintaining controlled differentiation through regulated protein levels.
2Productivity
If dormant horizontal basal cells are activated to become multipotent, then they can regenerate olfactory sensory neurons, but they require downmodulation of ΔNp63 which may affect cell stability
Solution Approach 1:
The patent applies dynamic control by using inducible systems (such as tamoxifen-inducible Cre-ERT2) to regulate ΔNp63 downmodulation. This allows reversible and controlled activation of HBCs, enabling the cells to transition between quiescent and multipotent states as needed, thereby maintaining stability while enabling productivity when required.
3Reliability
If agents that downmodulate ΔNp63 are administered to activate HBCs, then olfactory dysfunction is treated, but the complexity of the treatment protocol increases
Solution Approach 1:
The patent uses intermediary molecules such as microRNAs (particularly miR-203) and small molecules that specifically downmodulate ΔNp63. These intermediaries act as mediators between the administered agent and the ΔNp63 protein, providing targeted and specific activation of HBCs while simplifying the treatment protocol compared to direct genetic manipulation approaches.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
Activating dormant horizontal basal cells promotes adult neurogenesis and treats olfactory dysfunction by enabling them to regenerate olfactory sensory neurons, addressing age-related and injury-induced olfactory disorders.
Implementation Method 1
the agent(s) is an RNAi. In one embodiment, the agent(s) is a micro RNA. In one embodiment, the microRNA is micro RNA 203
Data Source
AI summary
Disclosed herein is a method for activating a dormant epithelial stem cell, or population thereof, to a state of multipotency comprising, reducing the level of ΔNp63 in the cell(s). The dormant epithelial stem cell(s) may be a horizontal basal cell (HBC) of the olfactory epithelium and the level of ΔNp63 may be reduced by contacting the cell or population with an effective amount of one or more agents that downmodulate ΔNp63. One example of an agent is an RNAi. Also disclosed is a method for treating olfactory dysfunction in a subject, comprising activating HBCs of the subject by reducing the level of ΔNp63 in one or more HBCs of the subject, to thereby treat the olfactory dysfunction. Activated horizontal basal cell (HBCs) are also disclosed.