Adenosine kinase as a target for therapeutic antisense strategies in epilepsy

Panos Theofilas, Sukhmani Brar, Kerry Ann Stewart, Hai Ying Shen, Ursula S. Sandau, David Poulsen, Detlev Boison

Research output: Contribution to journalArticlepeer-review

Abstract

Purpose: Given the high incidence of refractory epilepsy, novel therapeutic approaches and concepts are urgently needed. To date, viral-mediated delivery and endogenous expression of antisense sequences as a strategy to prevent seizures have received little attention in epilepsy therapy development efforts. Here we validate adenosine kinase (ADK), the astrocyte-based key negative regulator of the brain's endogenous anticonvulsant adenosine, as a potential therapeutic target for antisense-mediated seizure suppression. Methods: Wedeveloped adenoassociated virus 8 (AAV8)-based gene therapy vectors to selectively modulate ADK expression in astrocytes. Cell type selectivity was achieved by expressing an Adk-cDNA in sense or antisense orientation under the control of an astrocyte-specific gfaABC1D promoter. Viral vectors where injected into the CA3 of wild-type mice or spontaneously epileptic Adk-tg transgenic mice that overexpress ADK in brain. After virus injection, ADK expression was assessed histologically and biochemically. In addition, intracranial electroencephalography (EEG) recordings were obtained. Key Findings: We demonstrate in wild-type mice that viral overexpression of ADK within astrocytes is sufficient to trigger spontaneous recurrent seizures in the absence of any other epileptogenic event, whereas ADK down-regulation via AAV8-mediated RNA interference almost completely abolished spontaneous recurrent seizures in Adk-tg mice. Significance: Our data demonstrate that modulation of astrocytic ADK expression can trigger or prevent seizures, respectively. This is the first study to use an antisense approach to validate ADK as a rational therapeutic target for the treatment of epilepsy and suggests that gene therapies based on the knock down of ADK might be a feasible approach to control seizures in refractory epilepsy. Wiley Periodicals, Inc.

Original languageEnglish (US)
Pages (from-to)589-601
Number of pages13
JournalEpilepsia
Volume52
Issue number3
DOIs
StatePublished - Mar 2011
Externally publishedYes

Keywords

  • AAV8
  • ADK
  • Adenoassociated virus
  • Gene therapy
  • RNAi
  • Seizure

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

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