Targeting epilepsy with phototherapeutics

Introduction

As photo-activatable drugs (PDs) can be precisely controlled in space and time, caged and switchable photoactivatable drugs (CPDs, SPDs) are rapidly emerging as potential therapeutics for varied forms of cancer, vision loss, diabetes, or pain disorders.

Potential in Epilepsy

Despite their potential, PDs have not been exploited for epilepsy, a common, often debilitating neurological disorder. As 30% of epilepsies are medically intractable, and antiepileptic drugs often cause multi-organ side effects, PDs could break new therapeutic ground.

Advantages of PDs

1. PDs can be applied on demand.
2. They can be locally activated/inactivated in single or multiple epileptic brain areas in a targeted fashion.
3. This minimizes systemic side effects.
4. It allows the application of potent drugs from other fields yet unthinkable in routine epileptology (e.g., general anesthetics).

Importantly, being small molecules, different PDs can be combined or easily exchanged, and do not require protein expression.

Research Objectives

Using current and new PDs, we aim to control epileptic networks in vivo in a realistic epilepsy mouse model, and resected human brain tissue from patients with intractable epilepsy.

Aim 1

Aim 1 will quantify the antiepileptic potency of a range of PDs in human tissue using:

• Field potential recordings
• Patch-clamp recordings
• Cellular scale 2-photon imaging

Aim 2

In aim 2, PDs will be evaluated in vivo using:

• Wireless video-EEG
• Imaging
• Light-fiber-targeted drug photoactivation in chronically epileptic mice

Exploring Disease Modification

Further, by use of caged immunomodulators, we will explore the disease-modifying capacity of targeted PD photoactivation in epileptogenesis and chronic epilepsy.

Conclusion

PhotoTherEpi will establish targeted photopharmacology as a versatile and powerful new approach to control focal epilepsy, which could jumpstart a new branch of translational epilepsy research. The approach could obviate the need for resective surgery in many cases and be used in multi-focal epilepsy. Importantly, it may be clinically tested in the foreseeable future.