Abstract
Methamphetamine (METH) substance abuse disorders have major impact on society, yet no medications have proven successful at preventing METH relapse or cravings. Anti-METH monoclonal antibodies can reduce METH brain concentrations; however, this therapy has limitations, including the need for repeated dosing throughout the course of addiction recovery. An adeno-associated viral (AAV)-delivered DNA sequence for a single-chain variable fragment could offer long-term, continuous expression of anti-METH antibody fragments. For these studies, we injected mice via tail vein with 1 x 1012 vector genomes of two AAV8 scFv constructs and measured long-term expression of the antibody fragments. Mice expressed each scFv for at least 212 days, achieving micromolar scFv concentrations in serum. In separate experiments 21 days and 50 days after injecting mice with AAV-scFvs mice were challenged with METH in vivo. The circulating scFvs were capable of decreasing brain METH concentrations by up to 60% and sequestering METH in serum for 2 to 3 hrs. These results suggest that AAV-delivered scFv could be a promising therapy to treat methamphetamine abuse.
Highlights
Methamphetamine (METH) is a synthetic drug that causes periods of euphoria and stimulation, leading to very high abuse and a wide range of substance use disorders
Serum samples were analyzed via rapid equilibrium dialysis (RED) to determine METH binding capability
We present the design and in vivo characterization of two potentially therapeutic anti-METH monoclonal antibodies (mAbs)-based gene therapies
Summary
Methamphetamine (METH) is a synthetic drug that causes periods of euphoria and stimulation, leading to very high abuse and a wide range of substance use disorders. These METH associated medical problems result in devastating socioeconomic consequences for individuals, families, and communities. METH acts at multiple sites in the brain, and research attempts to design small molecule receptor agonist or antagonists have not yet lead to any FDAapproved medications that can reduce relapse or craving.[1,2] Cognitive-behavioral therapy is a mainstay of METH addiction treatment, but is of limited help since most patients relapse.
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