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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS058780-04
Application #
7989384
Study Section
Clinical Neuroscience and Disease Study Section (CND)
Program Officer
Fureman, Brandy E
Project Start
2008-01-01
Project End
2011-11-30
Budget Start
2010-12-01
Budget End
2011-11-30
Support Year
4
Fiscal Year
2011
Total Cost
$302,805
Indirect Cost
Name
Emanuel Hospital and Health Center
Department
Type
DUNS #
050973098
City
Portland
State
OR
Country
United States
Zip Code
97232
Pritchard, Eleanor M; Hu, Xiao; Finley, Violet et al. (2013) Effect of silk protein processing on drug delivery from silk films. Macromol Biosci 13:311-20
Vidal, Guillaume; Blanchi, Thomas; Mieszawska, Aneta J et al. (2013) Enhanced cellular adhesion on titanium by silk functionalized with titanium binding and RGD peptides. Acta Biomater 9:4935-43
Boison, Detlev (2013) Role of adenosine in status epilepticus: a potential new target? Epilepsia 54 Suppl 6:20-2
Boison, Detlev (2012) Adenosine dysfunction in epilepsy. Glia 60:1234-43
Boison, Detlev (2011) Modulators of nucleoside metabolism in the therapy of brain diseases. Curr Top Med Chem 11:1068-86
Boison, Detlev (2011) Methylxanthines, seizures, and excitotoxicity. Handb Exp Pharmacol :251-66
Shen, Hai-Ying; Lusardi, Theresa A; Williams-Karnesky, Rebecca L et al. (2011) Adenosine kinase determines the degree of brain injury after ischemic stroke in mice. J Cereb Blood Flow Metab 31:1648-59
Pritchard, Eleanor M; Valentin, Thomas; Boison, Detlev et al. (2011) Incorporation of proteinase inhibitors into silk-based delivery devices for enhanced control of degradation and drug release. Biomaterials 32:909-18
Theofilas, Panos; Brar, Sukhmani; Stewart, Kerry-Ann et al. (2011) Adenosine kinase as a target for therapeutic antisense strategies in epilepsy. Epilepsia 52:589-601
Masino, Susan A; Li, Tianfu; Theofilas, Panos et al. (2011) A ketogenic diet suppresses seizures in mice through adenosine A? receptors. J Clin Invest 121:2679-83

Showing the most recent 10 out of 27 publications