Transformed Probiotic Bacteria for Treatment of Chronic Diseases

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The continual increase in the number of patients suffering from chronic medical conditions that require long term treatment with therapeutic drugs such as hypercholesterolemia, hypertension, diabetes, and obesity has proven a tremendous economic burden, both to individuals and to health care systems. The traditional approach to drug production has been chemical synthesis of the needed compounds, then purification, formulation, and distribution. We propose to investigate a novel approach to long-term drug production and delivery: using probiotic intestinal bacteria transformed to express the required drug and inoculated into a patient for chronic colonization and therapeutic production. This approach essentially takes the notion of gene therapy and rather than altering the genomic DNA of the patient, instead alters the DNA of the patient's commensal bacteria, a far more tractable system. Probiotic intestinal bacteria such as members of the Lactobacillus family are routinely added to foods such as diary products, have essentially no pathology, and can be readily transformed with exogenous DNA. Lactobacillus transformed with therapeutic proteins and peptides or sets of enzymes to synthesize specific drugs may therefore represent a versatile platform for sustainable therapy. We will determine the optimal strains of Lactobacillus for expression in mice as a model organism and perform additional engineering of the strain as necessary to ensure persistence in the intestinal tract and regulated expression of peptide or proteins. We will also develop methods for rapidly depleting the transformed bacteria without damaging other commensal bacteria, as a safety precaution against the advent of any unexpected adverse responses during the use of these therapeutically transformed bacteria. We will then examine the effect on atherosclerosis-prone mice of expressing peptides with known therapeutic actions. Our final aim will be to test the feasibility of producing small molecule drugs such as lovastatin in vivo by transforming the bacteria with the required synthetic enzymes.