Adeno-associated virus-mediated expression of human butyrylcholinesterase to treat organophosphate poisoning

Autoři: Vibhor Gupta aff001;  C. Linn Cadieux aff002;  Deirdre McMenamin aff001;  C. Angelica Medina-Jaszek aff001;  Muhammad Arif aff001;  Omua Ahonkhai aff001;  Erik Wielechowski aff001;  Maryam Taheri aff001;  Yan Che aff001;  Tamara Goode aff001;  Maria P. Limberis aff001;  Mingyao Li aff001;  Douglas M. Cerasoli aff002;  Anna P. Tretiakova aff001;  James M. Wilson aff001
Působiště autorů: Gene Therapy Program, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America aff001;  United States Army Medical Research Institute of Chemical Defense, Maryland, United States of America aff002;  Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America aff003
Vyšlo v časopise: PLoS ONE 14(11)
Kategorie: Research Article
doi: 10.1371/journal.pone.0225188


Rare diseases defined by genetic mutations are classic targets for gene therapy. More recently, researchers expanded the use of gene therapy in non-clinical studies to infectious diseases through the delivery of vectorized antibodies to well-defined antigens. Here, we further extend the utility of gene therapy beyond the “accepted” indications to include organophosphate poisoning. There are no approved preventives for the multi-organ damage resulting from acute or chronic exposure to organophosphates. We show that a single intramuscular injection of adeno-associated virus vector produces peak expression (~0.5 mg/ml) of active human butyrylcholinesterase (hBChE) in mice serum within 3–4 weeks post-treatment. This expression is sustained for up to 140 days post-injection with no silencing. Sustained expression of hBChE provided dose-dependent protection against VX in male and female mice despite detectable antibodies to hBChE in some mice, thereby demonstrating that expression of hBChE in vivo in mouse muscle is an effective prophylactic against organophosphate poisoning.

Klíčová slova:

Antibodies – Blood plasma – Muscle proteins – Organophosphates – Poisoning – Prophylaxis – Gene therapy – Viral vectors


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2019 Číslo 11