Methamphetamine (METH) use disorder (MUD) continues to be a problem long after its initial surge in use. Various psychological therapies and the use of off-label drugs to treat MUD are currently the only treatments for MUD, which unfortunately can result in high rates of relapse within one year. A potential therapy to aid in recovery from MUD is the use of monoclonal antibodies capable of binding and sequestering METH in the blood stream. These antibodies, in theory, would prevent METH from reaching the brain and other tissues, and therefore prevent the effects that can prime relapse. While promising, this approach could have a complication of patient compliance, in that the half-life of monoclonal antibodies has been shown to be about three weeks in humans. Therefore, those recovering from MUD may experience various compliance issues. This issue of compliance led to the central aim of this dissertation: how can the duration of effect of an anti-METH antibody therapy be increased? To solve this problem, a gene therapy utilizing adeno associated viruses (AAV) was adopted. By administering AAV capsids packaged with anti-METH antibody DNA, host organisms can express the antibodies for at least 8 months with one injection. A short chain variable fragment (scFv) construct with high affinity to METH was first used. After analyzing the results, it was concluded that a greater circulating concentration of antibody would be required to provide clinically relevant levels of protection against METH. A second molecular design was undertaken to address the short half-life of the scFv construct resulting in an scFv-Fc fusion. For the scFv-Fc fusion we cloned an Fc region from a mouse IgG antibody to a scFv in one linear strand. Results from locomotor assays, showed that the AAV-scFv-Fc therapy decreased the potency of METH in mice by approximately 3 to 4-fold. The mice expressing the AAV-scFv-Fc therapy showed significantly less METH in their brains and sequestered significantly more METH in their serum than vehicle mice in a pharmacokinetics study. Further testing will be required to confirm the effectiveness and safety of the therapy before considering a human application.
|Advisor:||Peterson, Eric C|
|Commitee:||Fantegrossi, William E, Margaritis, Paris, Oliveto, Alison H, Owens, S Michael|
|School:||University of Arkansas for Medical Sciences|
|School Location:||United States -- Arkansas|
|Source:||DAI-B 81/10(E), Dissertation Abstracts International|
|Keywords:||Treat methamphetamine abuse|
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