Preclinical

CONRAD provides leadership in reproductive health by advancing microbicide candidates through preclinical discovery, clinical trials and bringing them to the marketplace. 

In 1988, CONRAD pioneered the microbicide research field by developing the first spermicide/virucide screening program. Since then, CONRAD’s network of scientists has evaluated more than 3,000 microbicide/contraceptive compounds. As a result of CONRAD’s extensive work evaluating microbicide candidates, a preclinical testing algorithm that includes assays to evaluate compounds for efficacy, cervicovaginal safety and pharmacokinetics and pharmacodynamics was developed and is now a reference for the field as a whole.

In Vitro Research: CONRAD has a pipeline of anti-HIV microbicide agents which are undergoing preclinical characterization, and is continuously adding new agents to target HIV. CONRAD has developed a network of investigators to ensure that any potential microbicide lead can be rapidly   characterized in terms of its antimicrobial, contraceptive and local safety properties. Additionally, investigation of biomarkers that potentially signal microbicide-induced mucosal damage is underway. 

Formulations: Microbicide candidates must be safe, efficacious, stable, and in a form acceptable to the patient. These characteristics, particularly challenging for delivering multiple active ingredients in a single vehicle, must be determined through stringent testing, including in vivo pharmacokinetic and toxicology studies. Currently, CONRAD scientists are working to develop multi-target combination microbicide products that are safe and that will inhibit HIV replication at different points along the virus life cycle, provide a strong barrier to the development of resistance, and remain stable within a suitable delivery system. 

Animal Models: Before microbicide candidates are tested in humans, they are tested in animal models to evaluate safety and efficacy. CONRAD is refining various animal models of vaginal infection by STD pathogens, including HIV, as part of the development necessary for attaining nontoxic, broad spectrum vaginal microbicides. Immune responses of small animals do not reliably predict those of people. Thus, the development of small animal models that can produce immune responses similar to those produced in humans is critical to determining how best to block HIV entry and transmission, and CONRAD scientists have been involved in these endeavors. Recent work has successfully humanized BLT mice, making them capable of producing human CD4(+) T cells that can be infected with HIV. CONRAD scientists are extending this model to study the effects of various microbicides and to determine how the herpes virus enhances HIV transmission in women. CONRAD researchers have successfully developed macaque models that are susceptible to HIV infection, which will improve understanding of the vaginal transmission of HIV and its blockage by antiretroviral microbicides.

Safety: CONRAD is committed to the development of safe vaginal microbicides. CONRAD researchers are working to improve preclinical safety assessments through the development, standardization and validation of in vitro and in vivo cell-based assays of cytotoxicity and proinflammatory cytokines. The Phase III trial of cellulose sulfate (CS), a microbicide targeting HIV, was stopped early due to ineffectiveness and possible harm. Prior safety trials had indicated neither property; consequently, CONRAD researchers are further analyzing the data to determine whether or not CS enhances HIV binding to dendritic cells, facilitates cell-associated transepithelial HIV infection, produces a subclinical inflammatory reaction, and/or changes microflora pathogenic outgrowths following repeated exposure. This work will inform the development of future microbicide candidates.