Oak Crest Institute Of Science

SYSTEMATIC DEVELOPMENT OF ANTIRETROVIRAL INTRAVAGINAL RINGS FOR HIV PREVENTION

A BIORESORBABLE SUBDERMAL IMPLANT FOR SUSTAINED DELIVERY OF A NOVEL MATURATION INHIBITOR TO PREVENT HIV INFECTION

SYSTEMIC SUSTAINED RELEASE DELIVERY OF ANTIRETROVIRAL AGENTS FOR HIV PREVENTION - ABSTRACT NEW HIV INFECTION RATES FAR OUTPACE THE TARGETS SET BY GLOBAL HEALTH ORGANIZATIONS, DESPITE IMPORTANT PROGRESS IN CURBING THE PROGRESSION OF THE EPIDEMIC. IN 2017, AN ESTIMATED 1.8 MILLION PEOPLE BECAME NEWLY HIV INFECTED GLOBALLY. NEW HIV PRE-EXPOSURE PROPHYLAXIS (PREP) STRATEGIES ARE NEEDED URGENTLY TO OVERCOME THIS ALARMING PREVENTION GAP. ADHERENCE TO DAILY DOSING REGIMENS HAS EMERGED AS A CRITICAL FACTOR DRIVING THE CLINICAL SUCCESS OF HIV-1 PREP WITH ANTIRETROVIRAL (ARV) DRUGS IN SUSCEPTIBLE, UNINFECTED INDIVIDUALS. THIS CHALLENGE CAN BE MITIGATED WITH SUSTAINED RELEASE OR “LONG-ACTING” ARV FORMULATIONS THAT REDUCE DOSING FREQUENCY, IDEALLY TO INTERVALS OF ONCE PER MONTH OR LONGER, AND TARGET THE HETEROGENEOUS POPULATIONS MOST AT RISK FROM CONTRACTING HIV. SEVERAL ARV DRUGS ARE UNDERGOING CLINICAL EVALUATION AS INJECTABLE SUSTAINED RELEASE FORMULATIONS, BUT SUFFER FROM A NUMBER OF DRAWBACKS: A HIGH INITIAL CONCENTRATION BURST; THE PARTICLES CANNOT BE REMOVED FOLLOWING INJECTION SHOULD THERE BE AN ADVERSE REACTION; THE APPROACH REQUIRES SPECIFIC ARV PHYSIOCHEMICAL CHARACTERISTICS, DRAMATICALLY LIMITING THE RANGE OF CANDIDATE DRUGS. MULTIPLE LARGE-SCALE CLINICAL TRIALS HAVE SHOWN THAT PREP USING ORAL PREPARATIONS OF THE NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITOR (NRTI) TENOFOVIR (TFV) CAN PREVENT HIV-1 INFECTION IN A SIGNIFICANT PROPORTION OF INDIVIDUALS. A LONG-ACTING TFV FORMULATION FOR SYSTEMIC DOSING WOULD ADD A MUCH-NEEDED NRTI TO THE PORTFOLIO OF SUSTAINED RELEASE PREP OPTIONS. UNDER PREVIOUS NIH SUPPORT WE HAVE DEVELOPED A SUBDERMAL IMPLANT DELIVERING THE HIGHLY POTENT PRODRUG TFV ALAFENAMIDE (TAF). WE HAVE EVALUATED THE PHARMACOKINETICS (PKS) AND SAFETY OF PROTOTYPE IMPLANTS DELIVERING TAF OVER A WIDE RANGE OF RELEASE RATES IN MICE, BEAGLE DOGS, AND SHEEP. THE DEVICES WERE SAFE IN THE TARGET DOSING WINDOW AND ALLOWED US TO SIMULATE A HUMAN DOSE FOR HIV-1 PREP. THE PROPOSED EFFORTS BUILD ON THESE IMPORTANT ACCOMPLISHMENTS AND WILL TEST THE CENTRAL HYPOTHESIS THAT A ONE-YEAR TAF IMPLANT WITH PRACTICAL PHYSICAL DIMENSIONS CAN SAFELY PREVENT SEXUAL HIV-1 INFECTION. IN AIM 1, WE WILL DESIGN THE NEXT GENERATION TAF IMPLANT TO MAXIMIZE DRUG LOADING AND CONTROL OF DRUG RELEASE USING SCALABLE PROCESSES AND ACCEPTABLE BIOMEDICAL MATERIALS. WE WILL CONDUCT PK STUDIES IN RATS AND SHEEP TO HELP SELECT LEAD CANDIDATES FOR EXTENSIVE SAFETY ASSESSMENT IN SHEEP UNDER AIM 2. HERE, THE IMPLANT MATERIALS AND EXCIPIENTS WILL BE EVALUATED TO MAXIMIZE LOCAL TOLERANCE IN VIVO, INCLUDING USING INNOVATIVE TARGETED PROTEOMIC/METABOLOMIC AND NON-INVASIVE IMAGING METHODS. IN AIM 3, HIV-1 (SHIV) PREVENTION EFFICACY STUDIES WILL BE CARRIED OUT IN RHESUS MACAQUES USING REPEAT LOW DOSE RECTAL, VAGINAL, AND PENILE EXPOSURE MODELS. THE PK-PHARMACODYNAMIC RELATIONSHIPS WILL BE INVESTIGATED IN EXPLORATORY MODELS. THE PROJECT WILL ADVANCE OUR SCIENTIFIC KNOWLEDGE ON THE PHARMACOLOGIC PROPERTIES OF SUSTAINED RELEASE SYSTEMIC TAF AND ITS METABOLITES COMPARED WITH ORAL FORMULATIONS IN THE CONTEXT OF HIV-1 PREVENTION.

SYSTEMIC SUSTAINED RELEASE DELIVERY OF ANTIRETROVIRAL AGENTS FOR HIV PREVENTION

NEXT GENERATION MULTIPURPOSE PREVENTION TECHNOLOGY: AN INTRAVAGINAL RING FOR HIV PREVENTION AND NONHORMONAL CONTRACEPTION

SUSTAINED RELEASE OF POTENT ANTIVIRAL PRODRUGS FOR HIV PREVENTION - ABSTRACT IMPORTANT PROGRESS IN CURBING THE PROGRESSION OF THE HIV EPIDEMIC HAS BEEN ACHIEVED, BUT NEW HIV INFECTION RATES ARE OUTPACING THE TARGETS SET BY GLOBAL HEALTH ORGANIZATIONS: IN 2019, AN ESTIMATED 1.7 MILLION PEOPLE BECAME NEWLY HIV INFECTED WORLDWIDE. NEW HIV PRE-EXPOSURE PROPHYLAXIS (PREP) STRATEGIES ARE NEEDED URGENTLY TO OVERCOME THIS ALARMING PREVENTION GAP. ADHERENCE TO DAILY DOSING REGIMENS HAS BEEN A CRITICAL IMPEDIMENT TO SUCCESS IN PREVIOUS HIV PREP CLINICAL TRIALS WITH ANTIRETROVIRAL (ARV) DRUGS IN SUSCEPTIBLE, UNINFECTED INDIVIDUALS. THIS CHALLENGE CAN BE MITIGATED WITH SUSTAINED RELEASE, OR LONG-ACTING, ARV FORMULATIONS THAT REDUCE DOSING FREQUENCY TO INTERVALS OF ONCE PER MONTH OR LONGER AND TARGET THE HETEROGENEOUS POPULATIONS MOST AT RISK FROM CONTRACTING HIV. AN INJECTABLE SUSTAINED RELEASE NANOPARTICLE FORMULATION OF THE ARV DRUG CABOTEGRAVIR RECENTLY HAS BEEN APPROVED BY THE US FDA FOR HIV PREP, BUT THIS TECHNOLOGY SUFFERS FROM A NUMBER OF DRAWBACKS: A HIGH INITIAL CONCENTRATION BURST; THE PARTICLES CANNOT BE REMOVED FOLLOWING INJECTION SHOULD THERE BE AN ADVERSE REACTION; PHARMACOKINETIC (PK) TAIL-PHASE WHERE SUB- THERAPEUTIC SYSTEMIC DRUG CONCENTRATIONS CAN PERSIST FOR OVER 1 YEAR AFTER THE LAST INJECTION. SUBDERMAL IMPLANTS WITH A DURATION OF USE OF SIX MONTHS OR LONGER ARE BEING DEVELOPED FOR HIV PREP USING A SINGLE AGENT; HOWEVER, EFFECTIVE STRATEGIES LIKELY WILL REQUIRE TWO ARV DRUGS. THIS BIOMEDICAL CHALLENGE IS EXACERBATED BY THE SCARCITY OF SAFE, EFFICACIOUS FDA-APPROVED AVAILABLE AGENTS WITH SUFFICIENT POTENCY TO ENABLE A FEASIBLE IMPLANT SIZE AND A PERIOD OF USE OF SIX MONTHS, OR LONGER. THE PROPOSED EFFORTS BUILD ON OUR PREVIOUS SUCCESSFUL ACCOMPLISHMENTS IN DEVELOPING SUSTAINED RELEASE DRUG DELIVERY BIOMEDICAL TECHNOLOGIES AND WILL TEST THE CENTRAL HYPOTHESIS THAT AN INNOVATIVE SUBDERMAL IMPLANT SYSTEM DELIVERING TWO, NEW POTENT ARV AGENTS WILL DEMONSTRATE INITIAL FEASIBILITY IN TERMS OF DRUG BIOPHYSICOCHEMICAL PROPERTIES AND EXPECTED DURATION OF USE. IN AIM 1, WE WILL DESIGN, SYNTHESIZE, AND SCREEN A LIBRARY OF NOVEL PRODRUGS BASED ON ESTABLISHED, FDA-APPROVED AGENTS FROM DIFFERENT MECHANISTIC CLASSES. LEAD CANDIDATES WILL BE SELECTED RATIONALLY USING A DECISION TREE BASED ON CLEARLY DEFINED, QUANTITATIVE RULES. IN AIM 2, PROMISING PRODRUG CANDIDATES WILL BE FORMULATED FOR SUSTAINED DELIVERY USING OUR NEXT-GENERATION SUBDERMAL IMPLANT SYSTEM, AND THESE EFFORTS WILL BE GUIDED BY USER PREFERENCE RESEARCH CONDUCTED IN SOUTH AFRICA TO FINE-TUNE MODIFIABLE DEVICE ATTRIBUTES. IN AIM 3, WE WILL CONDUCT PK AND SAFETY STUDIES IN MICE AND SHEEP, FOLLOWED BY EFFICACY STUDIES IN HUMANIZED MICE TO DETERMINE IF THE DEVICES CAN SAFELY PREVENT VAGINAL AND RECTAL HIV INFECTION. THE PROJECT BUILDS ON AN ESTABLISHED COLLABORATION OF HIGHLY EXPERIENCED INVESTIGATORS AND WILL ADVANCE OUR SCIENTIFIC KNOWLEDGE ON THE MANY, INTERRELATED ASPECTS OF SYSTEMIC, SUSTAINED DRUG DELIVERY FOR HIV PREVENTION.

A NOVEL, MULTI-COMPARTMENT INTRAVAGINAL RING FOR PREVENTION OF GENITAL HERPES AND UNINTENDED PREGNANCY - ABSTRACT GENITAL HERPES SIMPLEX VIRUS (HSV) INFECTION IS ONE OF THE MOST COMMON SEXUALLY TRANSMITTED INFECTIONS WORLDWIDE. THE INFECTION IS LIFELONG: THERE CURRENTLY IS NO CURE AND NO VACCINE. IN ADDITION, HSV-1 AND -2, HUMAN PAPILLOMAVIRUS (HPV), AND HUMAN IMMUNODEFICIENCY VIRUS (HIV) ARE RESPONSIBLE FOR INTERSECTING EPIDEMICS, WHERE THE DISEASE CAUSED BY ONE VIRUS FACILITATES THE TRANSMISSION AND/OR PATHOGENESIS OF THE OTHER. NUMEROUS STUDIES SUGGEST THAT USER-CONTROLLED MULTIPURPOSE PRODUCTS PROVIDING HSV PREVENTION –IDEALLY ALONG WITH HPV AND HIV– IN COMBINATION WITH CONTRACEPTION WOULD STRONGLY MOTIVATE HIGHER UPTAKE RELATIVE TO SINGLE-PURPOSE PRODUCTS: WOMEN NOT SELF-IDENTIFYING AS AT RISK OF HSV INFECTION WOULD USE A MULTIPURPOSE PRODUCT TO AVOID PREGNANCY, RESULTING IN SIGNIFICANTLY IMPROVED USER COMPLIANCE, AND HENCE EFFECTIVENESS, RELATIVE TO SINGLE-PURPOSE ANTIVIRAL PRODUCTS. MANY WOMEN WOULD PREFER A TOPICAL (VAGINAL) NONHORMONAL CONTRACEPTION METHOD THAT, UNLIKE VAGINAL GELS, DOES NOT REQUIRE USE IMMEDIATELY BEFORE OR AFTER SEX. OUR APPLICATION INTEGRATES KEY INNOVATIONS IN DEVELOPING A NEXT GENERATION MULTIPURPOSE TECHNOLOGY (MPT) INTRAVAGINAL RING (IVR) COMPRISED OF: (1) ANTIVIRAL PEPTIDE LEAD CANDIDATE WITH ACTIVITY AGAINST HSV, HPV, AND HIV; (2) SMALL-MOLECULE INHIBITORS OF SPERM FUNCTIONS REQUIRED TO REACH AND FERTILIZE THE OOCYTE; AND (3) A NOVEL IVR PLATFORM FOR LONG-ACTING, CONTROLLED DELIVERY OF THE TWO-DRUG COMBINATION. WE HAVE DESIGNED AND SYNTHESIZED A LIBRARY OF SMALL ANTIVIRAL PEPTIDES THAT DISRUPT A RANGE OF VIRUSES, INCLUDING HSV, HPV, AND HIV, AT LOW ΜM CONCENTRATIONS. AN EXISTING LEAD CANDIDATE, OPTIMIZED FOR VAGINAL DELIVERY, HAS BEEN SELECTED FOR IVR FORMULATION UNDER THE CURRENT APPLICATION. IN PARALLEL, WE HAVE DESIGNED AND SYNTHESIZED A LIBRARY OF HIGHLY POTENT, SMALL-MOLECULE INHIBITORS OF SOLUBLE ADENYLYL CYCLASE (SAC) THAT EFFECTIVELY BLOCK SPERM MOTILITY AND PREVENT IN VITRO FERTILIZATION AT SUB NM CONCENTRATIONS. FINALLY, OUR TEAM DEVELOPED AN INNOVATIVE IVR PLATFORM FOR THE DELIVERY OF DRUG COMBINATIONS, INCLUDING SMALL MOLECULES AND BIOMOLECULES, AT INDEPENDENTLY CONTROLLED RATES. IN AIM 1, WE WILL EVALUATE OUR PANEL OF SAC INHIBITOR LATE-LEAD CANDIDATES USING BIOCHEMICAL, FUNCTIONAL, AND PHARMACOLOGICAL ASSAYS TO SELECT A LEAD CANDIDATE DESIGNED SPECIFICALLY FOR VAGINAL DOSING. IN AIM 2, WE WILL FORMULATE AND EVALUATE IN VITRO HUMAN-SIZED MPT IVRS TO DELIVER OUR LEAD ANTIVIRAL PEPTIDE AND LEAD CONTRACEPTIVE COMBINATIONS AT TARGET IN VITRO RATES. IN AIM 3, WE WILL ASSESS THE PHARMACOKINETICS AND PHARMACODYNAMICS (SAFETY AND ANTI-HSV EFFICACY) OF MPT IVR CANDIDATES IN MICE (EFFICACY AND PRELIMINARY SAFETY) AND SHEEP (PHARMACOKINETICS AND SAFETY). THIS PROJECT BUILDS ON AN ESTABLISHED COLLABORATION OF INVESTIGATORS AND WILL ADVANCE OUR SCIENTIFIC KNOWLEDGE ON VAGINAL DELIVERY OF NOVEL AGENTS IN THE CONTEXT OF HSV PREVENTION AND NONHORMONAL CONTRACEPTION.

INTRAVAGINAL RING MICROBICIDE FORMULATIONS COMPRISING MULTIPLE ANTI-HIV AGENTS

EX VIVO MODEL FOR ASSESSING THE VAGINAL DISPOSITION OF PREP ANTIRETROVIRALS

MONROVIA - OAK CREST SCIENCE AND TECHNOLOGY INCUBATOR PROGRAM (MOST-IP)

INTRAVAGINAL RING MICROBICIDE FORMULATIONS COMPRISING MULTIPLE ANTI-HIV AGENTS

VAGINAL RING FORMULATION OF TENOFOVIR MICROBICIDE

COLLABORATIVE RESEARCH: HETEROGENEOUS PHOTOCATALYTIC TRANSFORMATION OF ISOPRENE: RELEVANCE TO SECONDARY ORGANIC AEROSOL FORMATION

NSF-REU SITE: RESEARCH EXPERIENCES FOR UNDERGRADUATES IN ENVIRONMENTAL SCIENCE AT THE OAK CREST INSTITUTE OF SCIENCE