title: Physiologic and metabolic safety of butyrylcholinesterase gene therapy in mice.
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 10(13) 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 40 mg/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.
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, USA; Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN 55905, USA. Electronic address: Murthy.Vishakantha@mayo.edu.
authors.forename: Vishakantha
authors.initials: V
authors.lastname: Murthy
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, USA; Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, USA; Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Liyi
authors.initials: L
authors.lastname: Geng
authors.affiliation: Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN 55905, USA; Department of Physical Medicine and Rehabilitation, Mayo Clinic, Rochester, MN 55905, USA; Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Nathan K
authors.initials: NK
authors.lastname: LeBrasseur
authors.affiliation: Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: White
authors.affiliation: Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
authors.forename: Robin J
authors.initials: RJ
authors.lastname: Parks
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, USA; Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Brimijoin
mesh_terms: D000256:Adenoviridae; D000818:Animals; D001481:Basal Metabolism; D002091:Butyrylcholinesterase / Q000235:genetics*; D003042:Cocaine / Q000378:metabolism; D019970:Cocaine-Related Disorders / Q000628:therapy*; D000229:Dependovirus; D004734:Energy Metabolism; D015316:Genetic Therapy; D005822:Genetic Vectors; D005951:Glucose Tolerance Test; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009043:Motor Activity; D010101:Oxygen Consumption; D019076:Transgenes
chemical_list: D002091:Butyrylcholinesterase; D003042:Cocaine
keywords: Adeno-associated viral vector; Butyrylcholinesterase; Cocaine addiction; Gene therapy; Helper-dependent adenoviral vector; Organophosphate toxicity