Stephen Brimijoin, Ph.D., is broadly interested in the molecular neurobiology, pharmacology and toxicology of cholinesterases, including the role of these enzymes in neurotransmission and their involvement in disease.
Early on, he and his team produced monoclonal antibodies that unexpectedly destroyed cholinergic pathways in rats, which led to a unique animal model for neuroimmunology. Later, they studied cholinesterases as biological targets of drugs, chemical warfare agents and pesticides, and also as active participants in neurological disorders.
They showed that acetylcholinesterase can promote deposits of brain amyloid in Alzheimer's disease and, with other Mayo Clinic investigators, worked to design new drugs to block this pathologic effect, creating a novel line of transgenic mice to test their therapeutic potential.
Dr. Brimijoin's current focus is developing modified cholinesterase molecules as agents for treatment of drug abuse. He and his colleagues helped re-engineer human plasma cholinesterase into a form that hydrolyzes cocaine fast enough to rescue rats from lethal overdose and prevent them from seeking cocaine as a reward.
Next, using mice and rats as animal models, they mounted an intense effort to determine whether viral gene transfer of these proteins can suppress psychological and behavioral responses to cocaine. Their most recent results show that it is possible to express hydrolases indefinitely in this way (i.e., for the life of a mouse or rat) at levels that block all observable responses to cocaine.
Significance to patient care
The major goal of Dr. Brimijoin and his collaborators is to lay the scientific basis for a clinically effective treatment that helps former users avoid the risk of relapse into drug addiction. They are now making major efforts to demonstrate efficacy and safety of cocaine hydrolase gene transfer and working toward an application to the Food and Drug Administration for an investigational new drug permit, preparatory to an eventual clinical trial.