title: Cocaine Hydrolase Gene Transfer Demonstrates Cardiac Safety and Efficacy against Cocaine-Induced QT Prolongation in Mice.
abstract: Cocaine addiction is associated with devastating medical consequences, including cardiotoxicity and risk-conferring prolongation of the QT interval. Viral gene transfer of cocaine hydrolase engineered from butyrylcholinesterase offers therapeutic promise for treatment-seeking drug users. Although previous preclinical studies have demonstrated benefits of this strategy without signs of toxicity, the specific cardiac safety and efficacy of engineered butyrylcholinesterase viral delivery remains unknown. Here, telemetric recording of electrocardiograms from awake, unrestrained mice receiving a course of moderately large cocaine doses (30 mg/kg, twice daily for 3 weeks) revealed protection against a 2-fold prolongation of the QT interval conferred by pretreatment with cocaine hydrolase vector. By itself, this prophylactic treatment did not affect QT interval duration or cardiac structure, demonstrating that viral delivery of cocaine hydrolase has no intrinsic cardiac toxicity and, on the contrary, actively protects against cocaine-induced QT prolongation.
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics, Robert and Arlene Kogod Center on Aging (V.M., L.G., Y.G., S.B.), and Marriott Heart Disease Research Program, Division of Cardiovascular Diseases (S.R.), Mayo Clinic, Rochester, Minnesota murthy.vishakantha@mayo.edu.
authors.forename: Vishakantha
authors.initials: V
authors.lastname: Murthy
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics, Robert and Arlene Kogod Center on Aging (V.M., L.G., Y.G., S.B.), and Marriott Heart Disease Research Program, Division of Cardiovascular Diseases (S.R.), Mayo Clinic, Rochester, Minnesota.
authors.forename: Santiago
authors.initials: S
authors.lastname: Reyes
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics, Robert and Arlene Kogod Center on Aging (V.M., L.G., Y.G., S.B.), and Marriott Heart Disease Research Program, Division of Cardiovascular Diseases (S.R.), Mayo Clinic, Rochester, Minnesota.
authors.forename: Liyi
authors.initials: L
authors.lastname: Geng
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics, Robert and Arlene Kogod Center on Aging (V.M., L.G., Y.G., S.B.), and Marriott Heart Disease Research Program, Division of Cardiovascular Diseases (S.R.), Mayo Clinic, Rochester, Minnesota.
authors.forename: Yang
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics, Robert and Arlene Kogod Center on Aging (V.M., L.G., Y.G., S.B.), and Marriott Heart Disease Research Program, Division of Cardiovascular Diseases (S.R.), Mayo Clinic, Rochester, Minnesota.
authors.forename: Stephen
authors.initials: S
authors.lastname: Brimijoin
mesh_terms: D000818:Animals; D003042:Cocaine / Q000633:toxicity*; D018014:Gene Transfer Techniques; D006867:Hydrolases / Q000235:genetics / Q000627:therapeutic use*; D008133:Long QT Syndrome / Q000139:chemically induced* / Q000235:genetics / Q000628:therapy*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016896:Treatment Outcome
chemical_list: D006867:Hydrolases; D003042:Cocaine