Encompassing basic science research, animal studies and clinical trials in adult patients, the new grant focuses on a potential Achilles' heel in the human immunodeficiency virus: sites on immune cells known as neurokinin-1 receptors. In focusing on those sites, researchers hope to achieve a triple benefit: fighting HIV by blocking the virus from immune cells, improving innate immune function and reducing symptoms of depression that are associated with the disease.
Steven D. Douglas, M.D., professor of Pediatrics, chief of the Section of Immunology and director of Clinical Immunology Laboratories at The Children's Hospital of Philadelphia, is the principal investigator and program director of the new Integrated Preclinical/Clinical Program grant. Dr. Douglas oversees projects led by collaborators at four sites: Children's Hospital, the University of Pennsylvania, Tulane National Primate Research Center, and Seracare Bioservices, Inc.
The program project is entitled, "Neurokinin-1R (SP Receptor) Antagonists for HIV Therapy." NIMH, a member institute of the National Institutes of Health, issued the four-year, $6.7 million grant award this fall.
The grant builds on more than a decade of investigation by Dr. Douglas into substance P, a neurotransmitter long known to be active in the brain and nervous system. Dr. Douglas and colleagues discovered in 1997 that immune cells produce substance P and its receptor, neurokinin-1, and later showed that incubation with substance P raised HIV levels in immune cell cultures. They subsequently found that a compound that binds to the substance P receptor in immune cells inhibits HIV from entering its hiding place within immune cells.
That compound, from a class of agents called neurokinin-1 receptor antagonists, may represent a new type of anti-HIV therapy, due to its ability to block HIV replication. The new program project grant will allow researchers to explore the potential of neurokinin-1 receptor (NK-1R) antagonists in a variety of ways.
In addition to studying direct antiviral action, the researchers will also look for effects on behavior. Because NK-1R antagonists are known to have antidepressant properties, any evidence of reduced anxiety-related behavior in animals may suggest potential important benefits for human HIV patients as well.
The grant includes four separate projects. Projects 1 and 2, led by virologist Wen-Zhe Ho, M.D., of Children's Hospital, and Dr. Douglas, respectively, aim to better understand the underlying mechanisms behind anti-HIV activity of NK-1R antagonists. The basic science research will particularly examine how these agents affect HIV-infected immune cells and how they also might protect the brain. "We know that substance P plays an important role in both the immune system and the central nervous system," said Dr. Douglas, "and we are testing the hypothesis that interfering with substance P receptors may reduce neurological injury from HIV infection."
Project 3, led by Andrew A. Lackner, Ph.D., D.V.M., director of the Tulane National Primate Research Center, will test whether NK-1R antagonists are safe in animals infected with simian immunodeficiency virus (SIV), which is analogous to HIV. This study aims to provide proof of concept for human trials under Project 4.
Project 4, led by Pablo Tebas, M.D., of the Department of Medicine at the University of Pennsylvania Medical School, will be a phase 1 (safety) trial of the NK-1R antagonist aprepitant (trade name Emend) in adults with HIV infection. Aprepitant is currently used to control nausea caused by chemotherapy; this project will determine whether the antagonist may also attack HIV infection in patients.
The grant also includes a private sector collaborator, Seracare Bioservices, Inc., of Gaithersburg, Md., for whom the principal investigator is Janet L. Lathey, Ph.D. This core laboratory will test candidate NK-1R drugs in conjunction with existing HIV drugs, evaluating antiviral activity against HIV-infected cells. "Including a private sector partner is a way to strengthen the goal of moving our scientific studies closer to clinical application," said Dr. Douglas.
Finally, a Biostatistics and Pharmacology Core serves all other components of the project. Directed by Avital Cnaan, Ph.D., with co-director Jeffrey Barrett, Ph.D., both of Children's Hospital, this core seeks to define linkages among the basic science experiments, the animal model experiments to establish pharmacology responses and the human trials designed to assess safety and activity.
The basic science projects of this four-year grant are already providing data, building on existing investigations of NK-1R antagonists. The animal model studies and clinical trials are in their initial stages.
The Children's Hospital of Philadelphia was founded in 1855 as the nation's first pediatric hospital. Through its long-standing commitment to providing exceptional patient care, training new generations of pediatric healthcare professionals and pioneering major research initiatives, Children's Hospital has fostered many discoveries that have benefited children worldwide. Its pediatric research program is among the largest in the country, ranking second in National Institutes of Health funding. In addition, its unique family-centered care and public service programs have brought the 430-bed hospital recognition as a leading advocate for children and adolescents. For more information, visit www.chop.edu.