Lactobacilli As A Delivery Vehicle For Microbicides
Qiang Xu
Osel, Inc. 4008 Burton Drive Santa Clara, Ca 95054
Grant 5U19AI060615-04 from National Institute Of Allergy And Infectious Diseases IRG: ZRG1
Abstract: In response to PAR-03-137, we are submitting a program proposal to design and develop a series of potent and highly selective protein-based topical microbicides. The unifying theme of the application is the use of non-pathogenic mucosal bacteria, lactobacilli, to deliver these proteins to mucosal surfaces within the vagina and rectum. The administration of genetically modified vaginal isolates of lactobacilli, expressing protein microbicides, is anticipated to prevent access or entry of HIV into host cells and tissues, thereby reducing infection. The three highly integrated projects include 1) an approach to design and develop lactobacilli expressing CD4 variants capable of a multivalent high-avidity interaction with HIV, as a means of trapping and inactivating HIV particles within the mucosa, 2) a program to produce lactobacilli expressing RANTES analogs that function as chemokine receptor antagonists and block HIV entry into cells and tissues of the host and 3) a project centered on lactobacillus-directed delivery of anti-ICAM derivatives as a novel means of inhibiting cell-associated mucosal transmission of HIV. These projects all will be supported by central core facilities, including administrative, microbiology, and primate safety study cores. Importantly, the three unique projects highlighted in this application have already completed key "proof-of-concept" studies that set the stage for the advanced research and development activities outlined in this application. Furthermore, all three approaches target conserved functional mechanisms used by HIV to achieve a productive infection of its host. As such, these approaches are less likely to be circumvented by the high mutability of viral proteins, an important property of HIV that has impaired the development of effective preventative vaccines.
Keywords: HIV infection, Lactobacillus, antiAIDS agent, biotherapeutic agent, communicable disease control, communicable disease transmission, cooperative study, drug design /synthesis /production, drug vehicle, topical drug application, biotechnology
Project start date: 2004-07-15
Project end date: 2008-06-30
5U19AI060615-04 (2007): $1330931
Sponsored Links Excellgen http://Excellgen.com
Lactobacilli As A Delivery Vehicle For Microbicides
Qiang Xu
Osel, Inc. 4008 Burton Drive Santa Clara, Ca 95054
Grant 5U19AI060615-03 from National Institute Of Allergy And Infectious Diseases IRG: ZRG1
Abstract: In response to PAR-03-137, we are submitting a program proposal to design and develop a series of potent and highly selective protein-based topical microbicides. The unifying theme of the application is the use of non-pathogenic mucosal bacteria, lactobacilli, to deliver these proteins to mucosal surfaces within the vagina and rectum. The administration of genetically modified vaginal isolates of lactobacilli, expressing protein microbicides, is anticipated to prevent access or entry of HIV into host cells and tissues, thereby reducing infection. The three highly integrated projects include 1) an approach to design and develop lactobacilli expressing CD4 variants capable of a multivalent high-avidity interaction with HIV, as a means of trapping and inactivating HIV particles within the mucosa, 2) a program to produce lactobacilli expressing RANTES analogs that function as chemokine receptor antagonists and block HIV entry into cells and tissues of the host and 3) a project centered on lactobacillus-directed delivery of anti-ICAM derivatives as a novel means of inhibiting cell-associated mucosal transmission of HIV. These projects all will be supported by central core facilities, including administrative, microbiology, and primate safety study cores. Importantly, the three unique projects highlighted in this application have already completed key "proof-of-concept" studies that set the stage for the advanced research and development activities outlined in this application. Furthermore, all three approaches target conserved functional mechanisms used by HIV to achieve a productive infection of its host. As such, these approaches are less likely to be circumvented by the high mutability of viral proteins, an important property of HIV that has impaired the development of effective preventative vaccines.
Keywords: HIV infection, Lactobacillus, antiAIDS agent, biotherapeutic agent, communicable disease control, communicable disease transmission, cooperative study, drug design /synthesis /production, drug vehicle, topical drug application, biotechnology
Project start date: 2004-07-15
Project end date: 2008-06-30
5U19AI060615-03 (2006): $1463248
5U19AI060615-02 (2005): $1345292
Grants awarded to Qiang Xu
DEVELOPMENT OF BACTERIAL THERAPEUTICS TARGETING BACTERIAL VAGINOSIS-ASSOCIATED BI
Qiang Xu, Director, Mucocept Research
Osel, Inc., 4008 Burton Drive, Santa Clara, Ca 95054
Grant 1R43AI089146-01 from National Institute Of Allergy And Infectious Diseases
Abstract: This application focuses on the development of a novel bacterial therapeutics targeting bacterial vaginosis (BV)-associated biofilm for the prevention and treatment of recurrent BV using a novel strain of Lactobacillus jensenii with a disrupted pox1 gene in the chromosome that exhibits highly potent activity against a Gardnerella vaginalis strain (ATCC 14018). As an important step to pursue this biofilm intervention strategy, we propose to further evaluate in vitro efficacy of this novel strain to inhibit clinical vaginal isolates of G. vaginalis and Atopobium vaginae in a co-culture model, and ability to prevent the development of Gardnerella- specific biofilm. BV is the most common infection of the reproductive tract among women of childbearing age globally. Control of BV recurrence has emerged as a global issue of concern, in light of its significant prevalence and pathophysiology among women of childbearing age. Epidemiologically, this disruption in vaginal ecology can lead to a serious disease burden of adverse obstetric and gynecologic outcomes, including adverse pregnancy outcomes and pelvic inflammatory disease. BV resembles a sexually transmitted disease (STD) and is positively associated with the acquisition of other STD. Moreover, BV is prominent in regions of the world associated with high HIV transmission rates and enhances viral replication and genital tract shedding of the HIV-1 and HSV-2 viruses, thereby further promoting the spread of STD. BV is a complex polymicrobial syndrome resulting from the depletion of the normal H2O2-producing lactobacilli in the vagina, overgrowth of BV-associated microorganisms, and the establishment of an adherent Gardnerella/Atopobium-specific biofilm. There are no long-term therapies for curing and preventing this frequently recurring BV condition. The recommended antibiotic treatments, the mainstay of current therapy, fail to eradicate biofilm that is an important predisposing factor for BV recurrence. There is an urgent need to develop innovative therapeutic approaches to target BV-associated biofilm. Successful completion of the proposed studies would position us to pursue potential clinical investigations to evaluate biofilm intervention strategies using bioengineered vaginal Lactobacillus. In combination with current antibiotic regimen, this product concept may have a great potential to shift current research or clinical practice paradigms for an effective treatment and prevention of recurrent BV globally. It would decrease the economical burden from repetitive treatments and potential adverse obstetric and gynecologic outcomes, while re-establishing a Lactobacillus-dominant healthy vaginal flora.
Keywords: AIDS Virus; Accounting; Acquired Immune Deficiency Syndrome Virus; Acquired Immunodeficiency Syndrome Virus; Anogenital venereal warts; Antibiotic Agents; Antibiotic Drugs; Antibiotic Resistance; Antibiotic Therapy; Antibiotic Treatment; Antibiotics; Atopobium vaginae; Bacteria; Bacterial Vaginosis; Biologic Products; Biological Agent; Biological Products; Biomedical Engineering; Biopsy; Body Tissues; California; Chlamydia; Chromosomes; Clinical; Clinical Trials; Clinical Trials, Phase II; Clinical Trials, Unspecified; Co-culture; Cocultivation; Coculture; Coculture Techniques; Collaborations; Communities; Complement; Complement Proteins; Complex; Condyloma Accuminata; Condylomata Acuminata; Corynebacterium vaginale; Development; Discipline of obstetrics; Disease; Disorder; Dysfunction; Ecology; Environmental Science; Evolution; Exhibits; FLR; Failure (biologic function); Female of child bearing age; Female of childbearing age; Functional disorder; Gardnerella; Gardnerella vaginalis; Genes; Genital; Genital System, Female, Vagina; Genital system; Genitourinary; Genitourinary system; Gonococcal Infection; Gonorrhea; Gynecologic; H2O2; HHV-2; HIV; HIV Entry Inhibitors; HIV-1; HIV-I; HIV1; HSV-2; HSV2; HTLV-III; Haemophilus vaginalis; Herpes Simplex Virus 2; Herpes Simplex Virus Type 2; Herpesvirus 2 (alpha), Human; Herpesvirus 2, Human; Herpesvirus progenitalis; Heterosexuals; Human; Human (alpha) herpes virus 2; Human Herpesvirus 2; Human Immunodeficiency Viruses; Human T-Cell Leukemia Virus Type III; Human T-Cell Lymphotropic Virus Type III; Human T-Lymphotropic Virus Type III; Human herpes simplex virus type 2; Human immunodeficiency virus 1; Human, General; Hydrogen Peroxide; Hydrogen Peroxide (H2O2); Hydroperoxide; Immunodeficiency Virus Type 1, Human; In Vitro; Infection; Intervention; Intervention Strategies; Investigation; LAV-HTLV-III; Lactobacillus; Lead; Length; Life; Light; Lymphadenopathy-Associated Virus; Man (Taxonomy); Man, Modern; Microbial Biofilms; Microorganisms, General; Miscellaneous Antibiotic; Miyagawanella; Modeling; Obstetrics; Organism; Outcome; Pb element; Pelvic Inflammatory Disease; Phase 2 Clinical Trials; Phase II Clinical Trials; Photoradiation; Physiopathology; Plasmids; Position; Positioning Attribute; Predisposing Factor; Pregnancy Outcome; Prevalence; Prevention; Public Health; Recurrence; Recurrent; Regimen; Reproductive Tract Infections; Research; Resistance to antibiotics; Resistance, Antibiotic; Resistant to antibiotics; STD; Sexually Transmitted Diseases; Sexually Transmitted Disorder; Sexually Transmitted Infection; Surface; Syndrome; System; System, LOINC Axis 4; Therapeutic; Tissues; Transmission; Trichomonas; UTI; Universities; Urinary tract infection; Urinary tract infectious disease; Urogenital; Urogenital System; Vagina; Vaginal; Vaginitis, Bacterial; Vaginitis, Nonspecific; Venereal Diseases; Venereal Disorders; Venereal Infections; Viral; Virus; Virus-HIV; Viruses, General; Warts, Genital; Warts, Venereal; Woman; Work; antibiotic resistant; bedsonia; bioengineering; bioengineering/biomedical engineering; biofilm; biopharmaceutical; biotherapeutic agent; burden of disease; burden of illness; clinical investigation; clinical practice; disease burden; disease/disorder; effective therapy; failure; heavy metal Pb; heavy metal lead; herpes simplex ii; human T cell leukemia virus III; human T lymphotropic virus III; human alphaherpesvirus 2; innovate; innovation; innovative; interventional strategy; living system; microbial; microbial community; microbicidal; microbicide; microorganism; novel; novel therapeutic intervention; pathophysiology; phase 2 study; phase 2 trial; phase II trial; prevent; preventing; protocol, phase II; public health medicine (field); public health relevance; study, phase II; therapeutic target; trait; transmission process; treatment of bacterial diseases; treatment of bacterial infectious disease; urogenital system (genital part); urogenital system (urinary part); vaginal lactobacilli; women of child bearing age; women of childbearing age; years of life lost to disability; years of life lost to disease
Relevance: 7. Bacterial vaginosis (BV) is the most common infection of the reproductive tract among women of childbearing age globally. Control of BV recurrence has emerged as a global issue of concern, in light of its significant prevalence and pathophysiology among women of childbearing age. There are no long-term therapies for curing and preventing this frequently recurring BV condition. The recommended antibiotic treatments, the mainstay of current therapy, are unable to eradicate a Gardnerella/Atopobium-specific biofilm and to prevent the recurrence of BV. There is an urgent need to develop innovative new therapeutic approaches to target BV- associated biofilm. The topic of our proposal is a novel strain of Lactobacillus jensenii with a disrupted pox1 gene in the chromosome that exhibits highly potent activity against a Gardnerella vaginalis strain (ATCC 14018). As an important step to pursue this biofilm intervention strategy, we propose to further evaluate in vitro efficacy of this novel strain to inhibit clinical vaginal isolates of G. vaginalis and Atopobium vaginae in a co-culture model, and its ability to prevent the development of Gardnerella-specific biofilm. Successful completion of the proposed studies would position us to pursue potential clinical investigations to evaluate biofilm intervention strategies using bioengineered vaginal Lactobacillus. In combination with current antibiotic regimen, this product concept may have a great potential to shift current research or clinical practice paradigms for an effective treatment and prevention of recurrent BV globally. It would decrease the economical burden from repetitive treatments and potential adverse obstetric and gynecologic outcomes, while re-establishing a Lactobacillus-dominant healthy vaginal flora
Project start date: 2010-08-01
Project end date: 2011-07-31
Budget start date: 1-AUG-2010
Budget end date: 31-JUL-2011
PFA/PA: RFA-OD-09-009
1R43AI089146-01 (2010): $198503
DEVELOPMENT OF A LIVE COMBINATIONAL MICROBICIDE FOR WOMEN
Qiang Xu, Director, Mucocept Research
Osel, Inc., 4008 Burton Drive, Santa Clara, Ca 95054
Grant 5R21AI079799-02 from National Institute Of Allergy And Infectious Diseases
Abstract: 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 (UTIs) and bacterial vaginosis (BV). Both UTIs and BV are associated with 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, currently under development, is a human vaginal isolate of H2O2-producing L. jensenii that has been genetically modified to constitutively secrete high levels of a single protein-based potent HIV envelope-targeted entry inhibitor, an N-terminally modified cyanovirin-N (CV-N) (P51G). This live, self-renewing microbicide may afford an efficacious, yet inexpensive means to deliver a protein-based microbicide and address the urgent need for female-controlled approaches to block heterosexual transmission of HIV-1. Among the microbicide candidates currently in clinical trials, almost all of them are "coital dependent" products, or are being formulated for development based on a single active ingredient. The need to develop "non-coital dependent" microbicides or combinational microbicides that act at multiple sites of the mucosal HIV infection pathway represents a significant gap in microbicide development. In this R21 proposal, we plan to develop a novel live combinational microbicide by employing an H2O2-producing vaginal L. jensenii 1153 genetically modified to constitutively secrete the N-terminally modified CV-N (P51G) and an effective CCR5- targeted entry inhibitor, C1C5-RANTES. The latter is an N-terminally modified RANTES that targets the major HIV co-receptor CCR5 with an increased antiviral and anti-inflammatory activity. In this proposal, we will explore the possibility of delivering CV-N and C1C5-RANTES from a single strain of Lactobacillus, or from a mixture of two strains, each delivering a single inhibitor. We will select a microbicide development candidate from a collection of bioengineered strains that contain optimized expression cassettes stably integrated into the L. jensenii chromosome. The R33 phase will follow after a successful completion of the proposed milestones in the R21 phase proposal. For the R33 phase, we propose to conduct preclinical animal safety and efficacy studies in mouse, rabbit, and non-human primates. We will employ a Chinese rhesus macaque (Macaca mulatta) model that allows persistent vaginal colonization of L. jensenii to conduct preclinical safety and efficacy studies, including in situ CV-N and C1C5-RANTES 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 which delivers combinational microbicides and to have a pre-IND consultation with FDA
Keywords: AIDS Virus; Acquired Immune Deficiency Syndrome Virus; Acquired Immunodeficiency Syndrome Virus; Address; Adherence; Adherence (attribute); Administration, Intravaginal; Administration, Vaginal; Animals; Anti-Inflammatories; Anti-Inflammatory Agents; Anti-inflammatory; Antiinflammatories; Antiinflammatory Agents; Antiviral Agents; Antiviral Drugs; Antivirals; Bacteria; Bacterial Chromosomes; Bacterial Vaginosis; Biologic Containment; Biologic Products; Biological Agent; Biological Containment; Biological Products; Biomedical Engineering; C-C CKR-5; C-C CKR-5 Gene; C-C Chemokine Receptor Type 5; C-C Chemokine Receptor Type 5 Gene; CC Chemokine Receptor 5; CC-CKR-5; CC-CKR-5 Gene; CC-CKR5; CCCKR5; CCCKR5 Gene; CCL5; CCR-5; CCR-5 Gene; CCR5; CCR5 Protein; CCR5 gene; CD195 Antigen; CD195 Antigen Gene; CHEMR13; CHEMR13 Gene; CKR-5; CKR-5 Gene; CKR5; CKR5 Gene; CMKBR5; CMKBR5 Gene; CV-N protein, Nostoc ellipsosporum; Cell Line; Cell Lines, Strains; CellLine; Cells; Cervical; Chemokine (C-C Motif) Ligand 5; Chemokine (C-C Motif) Receptor 5; Chemokine (C-C) Receptor 5; Chemokine (C-C) Receptor 5 Gene; Chinese; Chinese People; Chromosomes; Chromosomes, Bacterial; Clinical Trials; Clinical Trials, Phase II; Clinical Trials, Unspecified; Collection; Consultations; Cyanovirin-N; D17S136E; Development; Dose; Drug Formulations; Engineering; Engineerings; Entry Inhibitors, HIV; Epidemiologic Research; Epidemiologic Studies; Epidemiological Studies; Epidemiology Research; Epithelial Cells; Epithelium; Evaluation; Female; Formulation; Formulations, Drug; GMO Organisms; Generations; Genetic; Genetically Modified Organisms; Genital; Genital System, Female, Vagina; Genital system; H2O2; HIV; HIV Entry Inhibitors; HIV Infections; HIV-1; HIV-1 Fusion Co-Receptor; HIV-1 Fusion Co-Receptor Gene; HIV-I; HIV1; HTLV-III; HTLV-III Infections; HTLV-III-LAV Infections; Heterosexuals; Human; Human Immunodeficiency Viruses; Human T-Cell Leukemia Virus Type III; Human T-Cell Lymphotropic Virus Type III; Human T-Lymphotropic Virus Type III; Human immunodeficiency virus 1; Human, General; Hydrogen Peroxide; Hydrogen Peroxide (H2O2); Hydroperoxide; Immune; Immunodeficiency Virus Type 1, Human; In Situ; In Vitro; Individual; Infection; Intravaginal Administration; LAV-HTLV-III; Lactobacillus; Lead; Life; Lymphadenopathy-Associated Virus; MGC17164; Macaca mulatta; Mammals, Mice; Mammals, Rabbits; Man (Taxonomy); Man, Modern; Mice; Modeling; Murine; Mus; Opportunistic Infections; Organism; Organisms, Genetically Modified; Oryctolagus cuniculus; PBMC; Pathway interactions; Pb element; Peripheral Blood Mononuclear Cell; Pharmaceutical Agent; Pharmaceuticals; Pharmacologic Substance; Pharmacological Substance; Phase; Phase 2 Clinical Trials; Phase II Clinical Trials; Phenotype; Plasma, Seminal; Production; Proteins; RANTES; RANTES Protein, T-Cell; Rabbit, Domestic; Rabbits; Receptors, CCR5; Receptors, CKR5; Recurrence; Recurrent; Resistance; Rhesus; Rhesus Macaque; Rhesus Monkey; Risk; SCYA5; SHIV; SIS delta; SIS-delta; SISd; STD; Safety; Seminal Plasma; Sexually Transmitted Diseases; Sexually Transmitted Disorder; Sexually Transmitted Infection; Small Inducible Cytokine A5; T-Cell Specific Protein p288; T-Lymphotropic Virus Type III Infections, Human; TCP228; Therapeutic; Toxic effect; Toxicities; Transmission; UTI; Urinary tract infection; Urinary tract infectious disease; Vagina; Vaginal; Vaginitis, Bacterial; Vaginitis, Nonspecific; Variant; Variation; Venereal Diseases; Venereal Disorders; Venereal Infections; Viral; Virus-HIV; Woman; ing; base; biocompatibility; bioengineering; bioengineering/biomedical engineering; biomaterial compatibility; biopharmaceutical; biotherapeutic agent; candidate selection; clinical investigation; cultured cell line; design; designing; fitness; gene product; heavy metal Pb; heavy metal lead; human T cell leukemia virus III; human T lymphotropic virus III; immunogenicity; immunotoxicity; inhibitor; inhibitor/antagonist; irritation; living system; manufacturing process; microbial; microbicidal; microbicide; mucosal site; non-human primate; nonhuman primate; novel; pathogen; pathway; phase 2 study; phase 2 trial; phase II trial; pre-clinical; preclinical; preclinical safety; prevent; preventing; protein expression; protocol, phase II; resistant; self-renewal; simian HIV; simian human immunodeficiency virus; study, phase II; success; toxic reaction in immunology; transmission process; urogenital system (genital part); vaginal lactobacilli
Relevance: Osel, Inc. is developing a novel live combinational microbicide by genetically modifying a H2O2-producing vaginal Lactobacillus jensenii 1153 to constitutively secrete a potent HIV-envelope targeted inhibitor, an N- terminally modified cyanovirin-N (CV-N) (P51G), and an effective CCR5-targeted inhibitor, C1C5-RANTES. The latter is an N-terminally modified RANTES that targets the major HIV co-receptor CCR5 with an increased antiviral and anti-inflammatory activity. This live, self-renewing microbicide may afford an efficacious, yet inexpensive means to deliver a protein-based microbicide and address the urgent need for female-controlled approaches to block heterosexual transmission of HIV-1. We will explore the possibility of delivering this modified CV-N and C1C5-RANTES from a single strain of Lactobacillus, or from a mixture of two strains, each delivering a single inhibitor
Project start date: 2009-03-15
Project end date: 2011-02-28
Budget start date: 1-MAR-2010
Budget end date: 28-FEB-2011
PFA/PA: RFA-AI-08-016
5R21AI079799-02 (2010): $195122
DEVELOPMENT OF A LIVE TOPICAL MICROBICIDE FOR WOMEN
Qiang Xu
Osel, Inc., 4008 Burton Drive, Santa Clara, Ca 95054
Grant 5R33AI071978-04 from National Institute Of Allergy And Infectious Diseases
Abstract: 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
Keywords: AIDS Virus; Acquired Immune Deficiency Syndrome Virus; Acquired Immunodeficiency Syndrome Virus; Address; Adherence; Adherence (attribute); Animals; Antibiotic Agents; Antibiotic Drugs; Antibiotic Resistance; Antibiotics; Bacteria; Bacterial Vaginosis; Biologic Products; Biological Agent; Biological Products; Biomedical Engineering; CV-N protein, Nostoc ellipsosporum; Cell Line; Cell Lines, Strains; CellLine; Cervical; Chinese; Chinese People; Chromosomes; Clinical Trials, Phase II; Co-culture; Cocultivation; Coculture; Coculture Techniques; Collection; Consultations; Cyanovirin-N; Department of Health and Human Services; Department of Health and Human Services (U.S.); Development; Dose; Drug Evaluation; Drug Formulations; Drugs, Investigational; Epidemiologic Research; Epidemiologic Studies; Epidemiological Studies; Epidemiology Research; Epithelial Cells; Epithelium; Evaluation Research; Evaluation Studies, Drug; Female; Formulation; Formulations, Drug; GMO Organisms; Generations; Genetic; Genetically Modified Organisms; Genital; Genital System, Female, Vagina; Genital system; Genome Stability; H element; H2O2; HHS; HIV; HIV Entry Inhibitors; HIV-1; HIV-I; HIV1; HTLV-III; Heterosexuals; Human; Human Immunodeficiency Viruses; Human T-Cell Leukemia Virus Type III; Human T-Cell Lymphotropic Virus Type III; Human T-Lymphotropic Virus Type III; Human Volunteers; Human immunodeficiency virus 1; Human, General; Hydrogen; Hydrogen Peroxide; Hydrogen Peroxide (H2O2); Hydroperoxide; Immune; Immunodeficiency Virus Type 1, Human; In Situ; Infection; Investigational Drugs; Investigational New Drug Application; Investigational New Drugs; LAV-HTLV-III; Lactobacillus; Lead; Life; Local Microbicides; Lymphadenopathy-Associated Virus; Macaca mulatta; Man (Taxonomy); Man, Modern; Microbicides, Local; Miscellaneous Antibiotic; Modeling; Opportunistic Infections; Organism; Organisms, Genetically Modified; Pb element; Pharmaceutical Agent; Pharmaceuticals; Pharmacologic Substance; Pharmacological Substance; Phase; Phase 2 Clinical Trials; Phase II Clinical Trials; Proteins; Recombinants; Recurrence; Recurrent; Resistance to antibiotics; Resistance, Antibiotic; Resistant to antibiotics; Rhesus; Rhesus Macaque; Rhesus Monkey; Risk; SHIV; STD; Safety; Seminal Plasma; Sexually Transmitted Diseases; Sexually Transmitted Disorder; Sexually Transmitted Infection; Stability, Genomic; Therapeutic; Transference; Transference (Psychology); Transmission; UTI; United States Department of Health and Human Services; United States Dept. of Health and Human Services; Urinary tract infection; Urinary tract infectious disease; Vagina; Vaginal; Vaginitis, Bacterial; Vaginitis, Nonspecific; Venereal Diseases; Venereal Disorders; Venereal Infections; Viral; Virus-HIV; Woman; Work; antibiotic resistant; base; bioengineering; bioengineering/biomedical engineering; biomarker; biopharmaceutical; biotherapeutic agent; cultured cell line; design; designing; gene product; heavy metal Pb; heavy metal lead; human T cell leukemia virus III; human T lymphotropic virus III; immunogenicity; immunotoxicity; living system; manufacturing process; microbicidal; microbicide; non-human primate; nonhuman primate; novel; pathogen; phase 2 study; phase 2 trial; phase II trial; pre-clinical; preclinical; preclinical safety; preclinical study; prevent; preventing; protocol, phase II; self-renewal; simian HIV; simian human immunodeficiency virus; study, phase II; topical microbicide; toxic reaction in immunology; transmission process; urogenital system (genital part); vaginal lactobacilli; volunteer
Relevance: Osel, Inc. is developing a live microbicide by employing a human vaginal isolate of hydrogen peroxideproducing Lactobacillus jensenii that has been genetically modified to constitutively secrete high levels of a potent HIV entry inhibitor cyanovirin-N. This live microbicide may afford an efficacious, yet inexpensive and self-renewing delivery of protein-based microbicide to address the urgent need for female-controlled approaches to block heterosexual transmission of HIV-1
Project start date: 2007-09-30
Project end date: 2012-08-31
Budget start date: 1-SEP-2010
Budget end date: 31-AUG-2011
PFA/PA: RFA-AI-06-042
5R33AI071978-04 (2010): $345570
3R33AI071978-04S1 (2010): $425654
Development Of A Live Combinational Microbicide For Women
Qiang Xu
Osel, Inc.
Grant 1R21AI079799-01A1 from National Institute Of Allergy And Infectious Diseases IRG: ZAI1
Abstract: 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 (UTIs) and bacterial vaginosis (BV). Both UTIs and BV are associated with 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, currently under development, is a human vaginal isolate of H2O2-producing L. jensenii that has been genetically modified to constitutively secrete high levels of a single protein-based potent HIV envelope-targeted entry inhibitor, an N-terminally modified cyanovirin-N (CV-N) (P51G). This live, self-renewing microbicide may afford an efficacious, yet inexpensive means to deliver a protein-based microbicide and address the urgent need for female-controlled approaches to block heterosexual transmission of HIV-1. Among the microbicide candidates currently in clinical trials, almost all of them are "coital dependent" products, or are being formulated for development based on a single active ingredient. The need to develop "non-coital dependent" microbicides or combinational microbicides that act at multiple sites of the mucosal HIV infection pathway represents a significant gap in microbicide development. In this R21 proposal, we plan to develop a novel live combinational microbicide by employing an H2O2-producing vaginal L. jensenii 1153 genetically modified to constitutively secrete the N-terminally modified CV-N (P51G) and an effective CCR5- targeted entry inhibitor, C1C5-RANTES. The latter is an N-terminally modified RANTES that targets the major HIV co-receptor CCR5 with an increased antiviral and anti-inflammatory activity. In this proposal, we will explore the possibility of delivering CV-N and C1C5-RANTES from a single strain of Lactobacillus, or from a mixture of two strains, each delivering a single inhibitor. We will select a microbicide development candidate from a collection of bioengineered strains that contain optimized expression cassettes stably integrated into the L. jensenii chromosome. The R33 phase will follow after a successful completion of the proposed milestones in the R21 phase proposal. For the R33 phase, we propose to conduct preclinical animal safety and efficacy studies in mouse, rabbit, and non-human primates. We will employ a Chinese rhesus macaque (Macaca mulatta) model that allows persistent vaginal colonization of L. jensenii to conduct preclinical safety and efficacy studies, including in situ CV-N and C1C5-RANTES 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 which delivers combinational microbicides and to have a pre-IND consultation with FDA
Project start date: 2009-03-15
Project end date: 2011-02-28
DEVELOPMENT OF A LIVE TOPICAL MICROBICIDE FOR WOMEN
Qiang Xu, Director, Mucocept Research
Osel, Inc., 4008 Burton Drive, Santa Clara, Ca 95054
Grant 4R33AI071978-03 from National Institute Of Allergy And Infectious Diseases
Abstract: 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
Keywords: AIDS Virus; Acquired Immune Deficiency Syndrome Virus; Acquired Immunodeficiency Syndrome Virus; Address; Adherence; Adherence (attribute); Animals; Antibiotic Agents; Antibiotic Drugs; Antibiotic Resistance; Antibiotics; Bacteria; CV-N protein, Nostoc ellipsosporum; Cell Line; Cell Lines, Strains; CellLine; Cervical; Chinese; Chinese People; Co-culture; Cocultivation; Coculture; Coculture Techniques; Cyanovirin-N; Department of Health and Human Services; Department of Health and Human Services (U.S.); Development; Dose; Drug Evaluation; Drug Formulations; Drugs, Investigational; Entry Inhibitors, HIV; Epithelial Cells; Epithelium; Evaluation Research; Evaluation Studies, Drug; Female; Formulation; Formulations, Drug; GMO Organisms; Genetic; Genetically Modified Organisms; Genital; Genital System, Female, Vagina; Genital system; Genome Stability; H element; HHS; HIV; HIV Entry Inhibitors; HIV-1; HIV-I; HIV1; HTLV-III; Heterosexuals; Human; Human Immunodeficiency Viruses; Human T-Cell Leukemia Virus Type III; Human T-Cell Lymphotropic Virus Type III; Human T-Lymphotropic Virus Type III; Human Volunteers; Human immunodeficiency virus 1; Human, General; Hydrogen; Immune; Immunodeficiency Virus Type 1, Human; In Situ; Investigational Drugs; Investigational New Drug Application; Investigational New Drugs; LAV-HTLV-III; Lactobacillus; Lead; Life; Local Microbicides; Lymphadenopathy-Associated Virus; Macaca mulatta; Man (Taxonomy); Man, Modern; Microbicides, Local; Miscellaneous Antibiotic; Modeling; Organisms, Genetically Modified; Pb element; Pharmaceutical Agent; Pharmaceuticals; Pharmacologic Substance; Pharmacological Substance; Phase; Plasma, Seminal; Proteins; Recombinants; Research, Evaluation; Resistance to antibiotics; Resistance, Antibiotic; Resistant to antibiotics; Rhesus; Rhesus Macaque; Rhesus Monkey; SHIV; Safety; Seminal Plasma; Stability, Genomic; Transference; Transference (Psychology); Transmission; United States Department of Health and Human Services; United States Dept. of Health and Human Services; Vagina; Vaginal; Viral; Virus-HIV; Volunteers, Human; Woman; Work; antibiotic resistant; base; biomarker; cultured cell line; design; designing; gene product; heavy metal Pb; heavy metal lead; human T cell leukemia virus III; human T lymphotropic virus III; immunogenicity; manufacturing process; microbicidal; microbicide; non-human primate; nonhuman primate; novel; pre-clinical; preclinical; preclinical study; prevent; preventing; self-renewal; simian HIV; simian human immunodeficiency virus; topical microbicide; transmission process; urogenital system (genital part); volunteer
Relevance: Osel, Inc. is developing a live microbicide by employing a human vaginal isolate of hydrogen peroxideproducing Lactobacillus jensenii that has been genetically modified to constitutively secrete high levels of a potent HIV entry inhibitor cyanovirin-N. This live microbicide may afford an efficacious, yet inexpensive and self-renewing delivery of protein-based microbicide to address the urgent need for female-controlled approaches to block heterosexual transmission of HIV-1
Project start date: 2007-09-30
Project end date: 2012-08-31
Budget start date: 25-SEP-2009
Budget end date: 31-AUG-2010
PFA/PA: RFA-AI-06-042
4R33AI071978-03 (2009): $339396
5R21AI071978-02 (2008): $203512
1R21AI071978-01A1 (2007): $198290
Lactobacilli As A Delivery Vehicle For Microbicides
Qiang Xu
Osel, Inc. 4008 Burton Drive Santa Clara, Ca 95054
Grant 1U19AI060615-01 from National Institute Of Allergy And Infectious Diseases IRG: ZRG1
Abstract: In response to PAR-03-137, we are submitting a program proposal to design and develop a series of potent and highly selective protein-based topical microbicides. The unifying theme of the application is the use of non-pathogenic mucosal bacteria, lactobacilli, to deliver these proteins to mucosal surfaces within the vagina and rectum. The administration of genetically modified vaginal isolates of lactobacilli, expressing protein microbicides, is anticipated to prevent access or entry of HIV into host cells and tissues, thereby reducing infection. The three highly integrated projects include 1) an approach to design and develop lactobacilli expressing CD4 variants capable of a multivalent high-avidity interaction with HIV, as a means of trapping and inactivating HIV particles within the mucosa, 2) a program to produce lactobacilli expressing RANTES analogs that function as chemokine receptor antagonists and block HIV entry into cells and tissues of the host and 3) a project centered on lactobacillus-directed delivery of anti-ICAM derivatives as a novel means of inhibiting cell-associated mucosal transmission of HIV. These projects all will be supported by central core facilities, including administrative, microbiology, and primate safety study cores. Importantly, the three unique projects highlighted in this application have already completed key "proof-of-concept" studies that set the stage for the advanced research and development activities outlined in this application. Furthermore, all three approaches target conserved functional mechanisms used by HIV to achieve a productive infection of its host. As such, these approaches are less likely to be circumvented by the high mutability of viral proteins, an important property of HIV that has impaired the development of effective preventative vaccines.
Keywords: HIV infection, Lactobacillus, antiAIDS agent, biotherapeutic agent, communicable disease control, communicable disease transmission, cooperative study, drug design /synthesis /production, drug vehicle, topical drug application, biotechnology
Project start date: 2004-07-15
Project end date: 2008-06-30
1U19AI060615-01 (2004): $1090934
MUCOCEPT: A LIVE TOPICAL MICROBICIDE FOR WOMEN
Qiang Xu, Director, Mucocept Research
Osel, Inc., 4008 Burton Drive, Santa Clara, Ca 95054
Grant 5U01AI066708-04 from National Institute Of Allergy And Infectious Diseases
Keywords: A Mouse; AIDS Virus; AIDS/HIV; AIDS/HIV problem; Acquired Immune Deficiency Syndrome Virus; Acquired Immunodeficiency Syndrome Virus; Adherence; Adherence (attribute); Anaerobic Bacteria; Antibiotic Agents; Antibiotic Drugs; Antibiotics; Bacteria, Anaerobic; Bacterial Chromosomes; Bacterial Vaginosis; Bacteriophages; Biologic Products; Biological Agent; Biological Preservation; Biological Products; CAPS; CV-N protein, Nostoc ellipsosporum; Capsules; Cervical; Characteristics; Chromosomes, Bacterial; Clinical Trials; Clinical Trials, Phase I; Clinical Trials, Unspecified; Cyanovirin-N; Development; Disabled Persons; Disabled Population; Disease; Disorder; Disruption; Doctor of Philosophy; Drug Formulations; Early-Stage Clinical Trials; Ecology; Environment; Environmental Science; Epithelium; FDA; Fermentation; Food and Drug Administration; Food and Drug Administration (U.S.); Formulation; Formulations, Drug; GMP; Generalized Growth; Generations; Genes; Genital System, Female, Vagina; Genitourinary; Genitourinary system; Genome Stability; Gonococcal Infection; Gonorrhea; Growth; Guanosine Monophosphate; Guanylic Acids; H2O2; HIV; HIV-1; HIV-I; HIV/AIDS; HIV/AIDS problem; HIV1; HTLV-III; Handicapped; Health; Heterosexuals; Human; Human Immunodeficiency Viruses; Human T-Cell Leukemia Virus Type III; Human T-Cell Lymphotropic Virus Type III; Human T-Lymphotropic Virus Type III; Human immunodeficiency virus 1; Human, General; Hydrogen Peroxide; Hydrogen Peroxide (H2O2); Hydroperoxide; Immunodeficiency Virus Type 1, Human; In Situ; In Vitro; Incidence; Investigators; LAV-HTLV-III; Lactic acid; Lactobacillus; Lead; Length; Life; Local Microbicides; Lymphadenopathy-Associated Virus; Macaca; Macaque; Mammals, Mice; Mammals, Primates; Mammals, Rabbits; Man (Taxonomy); Man, Modern; Medical; Mice; Microbicides, Local; Miscellaneous Antibiotic; Modeling; Mucosa; Mucosal Tissue; Mucous Membrane; Murine; Mus; Opportunistic Infections; Organism; Oryctolagus cuniculus; Pb element; Pelvic Inflammatory Disease; People with Disabilities; Persons with Disabilities; Ph.D.; PhD; Phages; Phase 1 Clinical Trials; Phase I Clinical Trials; Phase I Study; Phenotype; Play; Position; Positioning Attribute; Pregnancy Outcome; Preservation, Biologic; Preservation, Biological; Prevention; Primates; Production; Program Development; Proteins; Rabbit, Domestic; Rabbits; Rate; Recurrence; Recurrent; Research Personnel; Researchers; Risk; Role; SHIV; STD; Safety; Sexually Transmitted Diseases; Sexually Transmitted Disorder; Sexually Transmitted Infection; Site; Stability, Genomic; Syndrome; Technology; Testing; Therapeutic; Tissue Growth; Toxicology; Transmission; USFDA; UTI; United States Food and Drug Administration; Urinary tract infection; Urinary tract infectious disease; Urogenital; Urogenital System; Vagina; Vaginal; Vaginitis, Bacterial; Vaginitis, Nonspecific; Venereal Diseases; Venereal Disorders; Venereal Infections; Virus-HIV; Woman; Work; anaerobe; anti-microbial; antimicrobial; bacterial virus; biopharmaceutical; biotherapeutic agent; capsule (pharmacologic); clinical investigation; design; designing; disabled; disabled people; disease/disorder; experience; gene product; heavy metal Pb; heavy metal lead; human T cell leukemia virus III; human T lymphotropic virus III; immunogenicity; improved; in vivo; inhibitor; inhibitor/antagonist; innovate; innovation; innovative; irritation; living system; microbial community; new therapeutics; next generation therapeutics; non-human primate; nonhuman primate; novel therapeutics; ontogeny; pathogen; phase 1 study; phase 1 trial; phase I trial; pre-clinical; preclinical; preservation; prevent; preventing; protocol, phase I; prototype; simian HIV; simian human immunodeficiency virus; social role; topical microbicide; transmission process; urogenital system (urinary part); vaginal lactobacilli
Project start date: 2005-06-15
Project end date: 2010-05-31
Budget start date: 1-JUN-2008
Budget end date: 31-MAY-2010
PFA/PA: RFA-AI-04-047
5U01AI066708-04 (2008): $0
Sponsored Links Excellgen http://Excellgen.com
5U01AI066708-03 (2007): $574751
5U01AI066708-02 (2006): $583184
1U01AI066708-01 (2005): $599760