DEVELOPING MICRORNA-BASED ADVANCED THERAPIES FOR EPILEPSIES

Drug-resistant epilepsies remain a major clinical challenge, highlighting the need for innovative therapeutic strategies that go beyond conventional pharmacological approaches. MicroRNA-based technologies offer a promising route to achieve cell-type-specific and activity-dependent modulation of neuronal excitability, with potential advantages coming from using a neuron's own innate regulatory network, as well as specificity, longevity and durability. This work explores two complementary strategies for the development of advanced microRNA-guided therapies aimed at restoring network stability in epilepsy.

The first strategy focuses on harnessing endogenous microRNA activity to regulate the expression of therapeutic transgenes. By incorporating microRNA-responsive elements into plasmid-based expression systems, transgene output can be selectively restricted to defined cellular contexts and pathological states. This approach enables conditional expression of ion channel–based effectors designed to dampen neuronal hyperexcitability, while minimizing off-target expression in unaffected cells. Such microRNA-sensitive constructs provide a modular framework for achieving refined spatial and functional control over therapeutic gene delivery.
The second strategy investigates targeted inhibition of specific microRNA pathways to enhance inhibitory neurotransmission. Strategic suppression of microRNAs that constrain components of inhibitory signalling cascades offers a means to potentiate endogenous mechanisms of synaptic inhibition. By relieving post-transcriptional repression, this approach aims to rebalance excitation/inhibition dynamics and reduce seizure susceptibility without the need for exogenous gene overexpression.
Together, these complementary approaches illustrate the versatility of microRNA-based regulatory systems for epilepsy therapy. By leveraging endogenous regulatory networks, microRNA-guided interventions may enable next-generation treatments that are adaptable, cell-selective, and tailored to the underlying pathophysiology of diverse epileptic disorders.