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- All Subjects: Plants
- Creators: Mason, Hugh S
Description
Cocaine abuse affects millions of people with disastrous medical and societal consequences. Despite this, there is still no FDA-approved treatment to decrease the likelihood of relapse in rehabilitated addicts, and acute cocaine toxicity (overdose) is only symptomatically treated. Studies have demonstrated a promising potential treatment option with the help of the human serum enzyme butyrylcholinesterase (BChE), an enzyme capable of breaking down cocaine into biologically inactive side products. This activity of wild-type BChE, however, is relatively low. This prompted the design of variants of BChE which exhibit significantly improved catalytic activity against cocaine. Plants were used as a sustainable, scalable, affordable platform system to produce large amounts of human biologics such as these cocaine hydrolase variants of BChE. Using a tobacco relative, Nicotiana benthamiana, recombinant enzymes can be produced at quantities relevant to clinical use with desired kinetic properties. Next, the ability of the most promising plant-produced cocaine super hydrolase, pCocSH, to counter the lethal effects of cocaine overdose in vivo was tested. These studies revealed that this plant-produced enzyme can protect mice from an otherwise lethal dose of cocaine. Most excitingly, it was found that pCocSH can rescue mice from overdose when given immediately after the onset of cocaine-induced seizures. These studies provide in vitro and in vivo proof-of-principle for a promising plant-derived biologic to be used as a pharmacokinetic-based treatment for cocaine addiction-related diseases such as overdose.
ContributorsLarrimore, Katherine E (Author) / Mor, Tsafrir S (Thesis advisor) / Gaxiola, Roberto (Committee member) / Mason, Hugh S (Committee member) / Neisewander, Janet L (Committee member) / Arizona State University (Publisher)
Created2015
Description
Influenza is a deadly disease that poses a major threat to global health. The surface proteins of influenza A, the type most often associated with epidemics and pandemics, mutate at a very high frequency from season to season, reducing the efficacy of seasonal influenza vaccines. However, certain regions of these proteins are conserved between strains of influenza A, making them attractive targets for the development of a ‘universal’ influenza vaccine. One of these highly conserved regions is the ectodomain of the influenza matrix 2 protein (M2e). Studies have shown that M2e is poorly immunogenic on its own, but when properly adjuvanted it can be used to induce protective immune responses against many strains of influenza A. In this thesis, M2e was fused to a pair experimental ‘vaccine platforms’: an antibody fusion protein designed to assemble into a recombinant immune complex (RIC) and the hepatitis B core antigen (HBc) that can assemble into virus-like particles (VLP). The two antigens were produced in Nicotiana benthamiana plants through the use of geminiviral vectors and were subsequently evaluated in mouse trials. Mice were administered three doses of either the VLP alone or a 1:1 combination of the VLP and the RIC, and recipients of both the VLP and RIC exhibited endpoint anti-M2e antibody titers that were 2 to 3 times higher than mice that received the VLP alone. While IgG2a:IgG1 ratios, which can suggest the type of immune response (TH1 vs TH2) an antigen will elicit, were higher in mice vaccinated solely with the VLP, the higher overall titers are encouraging and demonstrate a degree of interaction between the RIC and VLP vaccines. Further research is necessary to determine the optimal balance of VLP and RIC to maximize IgG2a:IGg1 ratios as well as whether such interaction would be observed through the use of a variety of diverse antigens, though the results of other studies conducted in this lab suggests that this is indeed the case. The results of this study demonstrate not only the successful development of a promising new universal influenza A vaccine, but also that co-delivering different types of recombinant vaccines could reduce the total number of vaccine doses needed to achieve a protective immune response.
ContributorsFavre, Brandon Chetan (Author) / Mason, Hugh S (Thesis advisor) / Mor, Tsafrir (Committee member) / Chen, Qiang (Committee member) / Arizona State University (Publisher)
Created2019