Physiologic and metabolic safety of butyrylcholinesterase gene therapy in mice

Vishakantha Murthy, Yang Gao, Liyi Geng, Nathan K. LeBrasseur, Thomas A. White, Robin J. Parks, Stephen Brimijoin

Research output: Contribution to journalArticle

20 Scopus citations

Abstract

In continuing efforts to develop gene transfer of human butyrylcholinesterase (BChE) as therapy for cocaine addiction, we conducted wide-ranging studies of physiological and metabolic safety. For that purpose, mice were given injections of adeno-associated virus (AAV) vector or helper-dependent adenoviral (hdAD) vector encoding human or mouse BChE mutated for optimal cocaine hydrolysis. Age-matched controls received saline or AAV-luciferase control vector. At times when transduced BChE was abundant, physiologic and metabolic parameters in conscious animals were evaluated by non-invasive Echo-MRI and an automated "Comprehensive Laboratory Animal Monitoring System" (CLAMS). Despite high vector doses (up to 1013 particles per mouse) and high levels of transgene protein in the plasma (~1500-fold above baseline), the CLAMS apparatus revealed no adverse physiologic or metabolic effects. Likewise, body composition determined by Echo-MRI, and glucose tolerance remained normal. A CLAMS study of vector-treated mice given 40mg/kg cocaine showed none of the physiologic and metabolic fluctuations exhibited in controls. We conclude that neither the tested vectors nor great excesses of circulating BChE affect general physiology directly, while they protect mice from disturbance by cocaine. Hence, viral gene transfer of BChE appears benign and worth exploring as a therapy for cocaine abuse and possibly other disorders as well.

Original languageEnglish (US)
Pages (from-to)4155-4162
Number of pages8
JournalVaccine
Volume32
Issue number33
DOIs
StatePublished - Jul 16 2014

Keywords

  • Adeno-associated viral vector
  • Butyrylcholinesterase
  • Cocaine addiction
  • Gene therapy
  • Helper-dependent adenoviral vector
  • Organophosphate toxicity

ASJC Scopus subject areas

  • Molecular Medicine
  • Immunology and Microbiology(all)
  • veterinary(all)
  • Public Health, Environmental and Occupational Health
  • Infectious Diseases

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