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.

Butyrylcholinesterase gene transfer in obese mice prevents postdieting body weight rebound by suppressing ghrelin signaling

“…The present study revealed no deficiency in motor or cognition functions in vector-treated mice, and our previous work with the same agent revealed no physiologic side effects other than reduced aggression and longer life in treated mice (51,52). It is worth noting that ghrelin affects not only appetite and weight gain, but also mood, anxiety, fear, and aggression (38,53).…”

Systemic Safety of a Recombinant AAV8 Vector for Human Cocaine Hydrolase Gene Therapy: A Good Laboratory Practice Preclinical Study in Mice

“…Over the past 10 years, our group performed a series of dose-efficacy and safety experiments in rats and mice for AAV8-hCocH without finding any viral vector-related toxicity. [24][25][26][27] The present study was undertaken to seek further systemic safety data of these high vector doses to define the upper dose limit in the future human trials.…”

Biologics to treat substance use disorders: Current status and new directions

“…For instance, viral-mediated transfer of BChE did not show signs of motor, cognitive, or cardiovascular toxicity in mice and rats. [172][173][174][175] Despite promising pre-clinical proof of efficacy and safety, it is not yet clear whether gene transfer approaches will be acceptable by the FDA, EMA, or other regulatory agencies. To date, the FDA's Center for Biologics Evaluation and Research (CBER) has not yet approved any human gene therapy product for market.…”