PROJECT SUMMARY This research will be undertaken with the ultimate goal of FDA permission for a First-In-Human clinical trial of a gene therapy to aid treatment-seeking cocaine users in becoming and remaining abstinent. The basis of the therapy is a virus-mediated gene transfer of a normal plasma enzyme whose ability to metabolize cocaine into harmless byproducts has been massively enhanced by 5 point mutations in the active site. Accumulated data from the investigator's laboratory indicates that such a treatment should be effective in reducing cocaine reward value to a point where even a compulsive user will be much less motivated to keep taking the drug. A wide range of toxicology and pathology data acquired in the same series of studies on mice, rats, and rhesus monkeys demonstrated NO adverse effects. These data were recently submitted to the FDA in a pre-IND package and discussed in a “pre-pre-IND teleconference” with Agency personnel who raised no firm objections to the proposed human trial. However FDA requested new data and repetition of key studies with vector produced under “good lab practice” (GLP) standards. The present proposal seeks funding to acquire the needed (large) amounts of vector for definitive preclinical studies carried out with professional quality assurance (QA). In addition, we are committed to paving the way for an initial human study with the validated final reagent, to be carried out by Drs. Tom Newton and Tom Kosten at Baylor College of Medicine. Thus all funds will go towards testing a promising new addiction therapy and carrying it across the threshold to clinical application.

PROJECT NARRATIVE Cocaine addiction continues to impose major burdens on affected individuals and society in general but is highly resistant to medical treatment or psychotherapy. Our lab has spearheaded efforts to devise and test a radical new gene transfer therapy for compulsive abuse by sustained expression of enzyme mutated to eliminate cocaine's reward value. We now aim to obtain definitive preclinical data to justify an Investigational New Drug permit from the U.S. Food and Drug Administration and to support a pilot study of the experimental therapy with current cocaine users.