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Abstract
Grant Number: 5R44AI046203-03 PI Name: MARTIN, PATRICK K. PI Email: pmartin@oselinc.com PI Title: Project Title: Neutralization of HIV by Modified Lactobacilli Abstract: DESCRIPTION: (Provided by Applicant) The predominant mode of HIV transmission worldwide is via heterosexual contact, with the cervicovaginal mucosa serving as the main site of viral entry in women. Realizing that the vaginal mucosa is colonized with large numbers of non-pathogenic lactobacilli, we propose an innovative approach toward blocking transmission of HIV that involves genetically modifying clinical isolates of lactobacillus to express proteins that bind and inactivate HIV prior to transmission to host tissues. We have been able to demonstrate that vaginal lactobacilli can be engineered to secrete a truncated form of the CD4 molecule (containing domains 1-2) that is capable of binding to the HIV virus and reducing the infectious titer in vitro. In so doing, we have provided the first demonstration of the expression of a complex disulfide-bonded, biologically active mammalian protein in lactobacillus. We now intend to transition this program into its early development phases to enable future clinical testing. Specifically, we propose the following aims: 1) express several other HIV binding proteins in L. jensenii and from efficacy data, select the optimal protein to carry forward; 2) integrate the ligand expression constructs into the chromosome of L. jensenii, using either selected inducible (e.g. alkaline shock) or strong, constitutive promoters (e.g. PcbsA) to drive expression from a single copy; and 3) develop pilot scale manufacturing process, including formulation, of these engineered lactobacilli. The successful completion of these proposed Phase II studies will position us for entry into clinical trials, where this novel ViroShield approach will meet its most rigorous evaluation. PROPOSED COMMERCIAL APPLICATION: NOT AVAILABLE
Thesaurus Terms:
AIDS education /prevention, Lactobacillus, gene delivery system, genetic manipulation, human immunodeficiency virus, mucosal immunity, technology /technique development, virus protein
CD4 molecule, communicable disease transmission, dosage forms, surface antigen, vagina, virus cytopathogenic effect
biotechnology, cell line, electroporation, female
Institution: OSEL, INC. SUITE 14 SANTA CLARA, CA 95054 Fiscal Year: 2003 Department: Project Start: 01-SEP-1999 Project End: 29-FEB-2004 ICD: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES IRG: ZRG1
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