Development of a Live Topical Microbicide for Women

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DESCRIPTION (provided by applicant): Osel, Inc. is a biopharmaceutical company specializing in the development of bacterial therapeutics. The company's lead product, LACTIN-V, is a naturally occurring human vaginal isolate of Lactobacillus crispatus presently undergoing phase II clinical trials to examine its safety and efficacy in preventing recurrent urinary tract infections and bacterial vaginosis (BV). Both of these infections are characterized by a depletion of hydrogen peroxide (H2O2)-producing lactobacilli that normally protect the vagina from infection by opportunistic pathogens. Epidemiological studies also suggest that loss of vaginal lactobacilli is associated with an increased risk of heterosexual HIV-1 transmission and other sexually transmitted infections. LACTIN-V represents an ecological approach to prevent vaginal infections by re-establishing the protective vaginal flora with a colonizing, H2O2-producing Lactobacillus strain. A second-generation Lactobacillus product, and the topic of this proposal, is a human vaginal isolate of H2O2-producing L. jensenii that has been genetically enhanced to constitutively secrete high levels of the potent HIV entry inhibitor cyanovirin-N (CV-N). This live, self-renewing microbicide may afford an efficacious, yet inexpensive means to deliver a protein-based microbicide and addresses the urgent need for female-controlled approaches to block heterosexual transmission of HIV-1. In this R21 proposal, we will select a microbicide development candidate from a collection of bioengineered strains that contain optimized CV-N expression cassettes stably integrated into the L. jensenii chromosome. We will employ a Chinese rhesus macaque (Macaca mulatta) model that affords persistent vaginal colonization of L. jensenii to conduct preclinical safety and efficacy studies, including in situ CV-N expression, immunotoxicity, and efficacy against mucosal viral transmission. Furthermore, we propose to evaluate potential regulatory issues concerning the pharmaceutical development of a genetically modified organism, and to optimize the formulation and manufacturing processes for this product. Following a pre-IND consultation with the FDA, we will file an exploratory IND application and then initiate two exploratory phase 0 studies in the R33 phase of the proposal to assess the effects of the recombinant L. jensenii strain on safety, tolerability, innate genital tract immune factors, vaginal colonization, and clearance of the organism after antibiotic administration in healthy female volunteers.