Suppression of pharmacoresistant seizures in mesial temporal lobe epilepsy (MTLE) remains a major challenge in epilepsy therapy. Adenosine is an endogenous neuromodulator with potent anticonvulsant properties and thus highly suited to meet this therapeutic need. However, due to peripheral side effects of adenosine, a local mode is needed to supplement adenosine to the brain.
We aim to develop biocompatible scaffolds to deliver the endogenous seizure suppressor adenosine to suppress seizures in a rat model of MTLE. The rationale for this approach is based on the following findings from our labs: (1) Deficits of adenosinergic neuromodulation, in particular upregulation of the main adenosine removing enzyme adenosine kinase, contribute to epileptogenesis and seizures. (2) Augmentation of adenosine is sufficient to suppress pharmacoresistant seizures. (3) Local delivery of approx. 200 ng adenosine per day by brain implants of adenosine releasing cells is sufficient to provide complete seizure suppression in a model of MTLE. (4) Stem cell derived brain implants engineered to release adenosine retard epileptogenesis. (5) The combination of biopolymers and engineered stem cells promotes the release of adenosine. (6) Polymer scaffolds and cell encapsulation matrices are available, which permit cell replacement and sustained local drug delivery. Our CENTRAL HYPOTHESIS is that local brain implants based on a combination of slow degrading biopolymers with adenosine and/or cells engineered to release adenosine are needed for clinical applications aimed at suppressing seizures in pharmacoresistant MTLE. The model system to address this hypothesis will consist of a novel protein-based polymer system, silk fibroin, in combination with adenosine and adenosine-producing cells, to be tested in an animal model of epilepsy.
Our SPECIFIC AIMS are:
Aim 1. Engineer biocompatible polymers for the local therapeutic delivery of adenosine.
Aim 2. Develop a polymer/cell based system for the sustained delivery of adenosine.
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