Preclinical

Advances in Preclinical Research

CONRAD provides leadership in reproductive health by advancing microbicide and contraceptive agents through preclinical discovery, clinical trials and bringing them to the marketplace. CONRAD scientists have been instrumental in moving forward a number of potential microbicide agents, including PRO2000, BufferGel, tenofovir, and UC781. 

In Vitro Research: CONRAD has a pipeline of anti-HIV microbicide and contraceptive agents, which are undergoing preclinical characterization, and is also adding new agents to target HIV, such as a substance previously used to treat protozoan diseases. CONRAD has also developed a network of investigators to ensure that any potential microbicide lead can have a rapid characterization of its antimicrobial, contraceptive and local safety properties. In 2008, the network screened 166 compounds or formulations and is testing a set of biomarkers that potentially signals microbicide-induced mucosal damage. 

Animal Models: Immune responses of small animals do not reliably predict those of people. Development of small animal models that can produce immune responses similar to those produced in humans is critical in 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 and having those cells become infected with HIV. CONRAD scientists are extending this model to study the effects of various microbicides and to determine how 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 anti-retroviral microbicides.

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 developing resistance, and remain stable within a suitable delivery system. 

Safety: The Phase III trial of cellulose sulfate (CS), a microbicide targeting HIV, was stopped due to ineffectiveness and possible harm. 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 to CS.

CONRAD scientists are researching how in vitro­ toxicity assays, proinflammatory cytokines and stages in the in vivo rabbit vaginal irritation model associate with markers in genital mucosa using relevant human epithelial cell lines to determine robust biomarkers for the local safety of microbicides.