Tet-a-TET: a silencing-resistant, doxycycline-inducible gene expression system for differentiated neurons
This technology is a next-generation doxycycline-inducible gene expression platform designed to overcome promoter silencing and enable robust, stable transgene expression for functional studies in post-mitotic neurons.
Unmet Need: Reliable, tunable gene expression system in differentiated neurons
Inducible gene expression systems are powerful tools for studying gene function, modelling disease processes, and evaluating therapeutic targets. However, achieving reliable and tunable gene expression in mature neurons remains a longstanding challenge, as commonly used drug-inducible systems, such as Tet-On often lose activity after neuronal differentiation. This is largely due to epigenetic silencing such as methylation of the tetracycline-responsive promoter (TRE), which reduces or abolishes downstream gene expression. Existing approaches only partially restore promoter activity, and expression levels are often low or inconsistent across neuronal populations.
The Technology: Silencing-resistant doxycycline-inducible gene expression system for mature neurons
This technology introduces Tet-a-TET, a next-generation doxycycline-inducible platform designed to overcome promoter silencing in mature neurons. The system recruits a demethylase catalytic domain to the TRE, preventing methylation-mediated promoter silencing and maintaining promoter accessibility before induction. Upon doxycycline treatment, the system switches to transcriptional activation, driving strong and uniform expression of the desired transgene. Tet-a-TET showed substantially improved gene activation compared with existing alternative systems and is compatible with stable integration strategies such as piggyBac transposon or AAVS1 safe-harbor approaches.
This technology has been validated in vitro in post-mitotic human motor neurons.
Applications:
- Inducible gene expression for neuronal functional genomics
- Disease modelling for neurodegenerative and neurological disorders
- Tunable expression of disease-linked, toxic, or dosage-sensitive proteins
- Platform for systematic, virus-free functional studies in differentiated neurons
- Platform for gene therapy optimization in mature neurons
Advantages:
- Resistant to promoter silencing in differentiated neurons
- Improved transgene activation rate
- Robust and uniform transgene expression after induction
- Tunable, dose-dependent control of gene expression
- Compatible with virus-free delivery and stable integration strategies
Lead Inventor:
Related Publications:
Tech Ventures Reference:
IR CU26148
Licensing Contact: Jerry Kokoshka