Focal Adenosine Augmentation Therapies to Treat Epilepsy
Research from our lab has demonstrated that deficiencies in the brain’s own adenosine-based seizure control system contribute to seizure generation. Consequently, reconstitution of adenosinergic neuromodulation constitutes a rational approach for seizure control. Therefore, focal adenosine augmentation therapies (AATs) have significant potential for antiepileptic and disease modifying therapy. Due to systemic side effects of adenosine, focal adenosine augmentation – ideally targeted to an epileptic focus – becomes a therapeutic necessity.
This has experimentally been achieved in kindled seizure models as well as in post status epilepticus models of spontaneous recurrent seizures using four different therapeutic strategies:
(i) Polymer-based brain implants that were loaded with adenosine;
(ii) Brain implants comprised of cells engineered to release adenosine and embedded in a cell-encapsulation device;
(iii) Direct transplantation of stem cells engineered to release adenosine; and
(iv) Knockdown of ADK in vivo using viral gene therapy vectors.
To meet the therapeutic goal of focal adenosine augmentation, genetic disruption of the adenosine metabolizing enzyme adenosine kinase (ADK) in rodent and human cells in vitro (ex vivo gene therapy) or directly in vivo (in vivo gene therapy) was used as a molecular strategy to induce focal adenosine augmentation, which demonstrated potent antiepileptic and neuroprotective properties.
Adenosine Augmentation Therapy