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MISSION AND SCIENTIFIC BACKGROUND
The Center for Research in Contraceptive and Reproductive Health [CRCRH, formerly CRGCV] provides an organizational framework to allow convergence and assembly of the various technologies and personnel required to identify contraceptive targets in the egg and sperm, to validate their candidacy as contraceptive immunogens and as targets for rational drug design, to formulate and test candidate vaccines and antagonists, and to transfer technology to industrial collaborators and thus to maximize the potential development of contraceptive vaccines and new generations of contraceptive drugs for humans. Organized along the development pathway for a vaccine or a pharmaceutical, the Center is engaged in fundamental discovery of new potential gamete targets and their antigenic determinants and/or functional domains, cloning and characterizing the genes encoding these proteins, validation of contraceptive candidacy through studies of tissue specificity, protein expression, scale-up, vaccine formulation, antagonist screening and selection, and fertility testing in small animals and primates. The Center has strategic alliances with industry which take advantage of a depth of resources and expertise in drug development and medicinal chemistry. The Center thus has in place a multi-disciplinary research program which spans the fields of cell and molecular biology, immunology, reproductive biology, chemical engineering, and structural biology. The Center is multi-institutional, with subprojects and cores at the University of North Carolina and Northwestern University as well as at the University of Virginia, the lead institution. The Center was formed in 1990 and has received support from a number of agencies including the National Institutes of Health, US Agency for International Development, CONRAD, the World Health Organization, the Andrew W. Mellon Foundation, the National Institute of Justice, The Kenneth Scott Charitable Trust and well as industrial sponsors including Schering AG, Organon, ContraVac and Genetics Savings & Clone.
Scientific Background: Rapid progress in the fields of molecular biology, reproductive and cellular biology, immunology, chemical engineering, structural biology, and combinatorial chemistry has laid a foundation for development of contraceptive vaccines and antagonists based upon target proteins unique to the gametes. Human genomic DNA sequence information indicates that the "draft" human genome contains an estimated 30,000 genes encoding roughly 140,000 proteins. Fewer than 500 of these proteins serve as targets for all of today's medicines. Opportunities for development of contraceptive vaccines and drugs remain locked in the extensive collection of functionally anonymous proteins known only through genomic DNA sequences. Differential display, gene chips, EST databases, virtual northern analyses and RT PCR have demonstrated the exquisite specificity of temporal and spatial expression of various genes, regulated by transcription factors and the methylation and acetylation of histones. The realization that selected proteins are transcribed and translated only at specified times during gametogenesis has opened opportunities to identify and target for contraceptive purposes proteins unique to the gametes. Indeed gametes even express tissue specific isoforms of several housekeeping enzymes that afford unique opportunities for drug targeting. The fields of functional genomics, transcriptomics, and proteomics are the foundations of the essential research mission of this center: to use the powerful tools of contemporary biology in the cause of identifying gamete specific proteins and testing novel vaccines and antagonists based on these contraceptive targets.
In the search for vaccinogens, monoclonal and polyclonal antibodies have allowed definition of specific sperm and egg molecules that play key roles in the processes of gamete development, sperm capacitation, and fertilization; recombinant DNA technology has made possible the definition and manipulation of the genetic material encoding these molecules; and advances in protein synthesis and in bioprocess development and product purification have made available sufficient quantities of recombinant proteins and synthetic peptides in relatively pure form. The emergence of protein microsequencing by tandem mass spectrometry has permitted small quantities of membrane proteins to be identified and cloned. Immunization with defined sperm antigens has resulted in 100% contraceptive efficacy in small animal models [guinea pigs]. Injections of recombinant and peptide vaccine immunogens in primates have produced strong and specific immune responses. Antibodies from primates inoculated with recombinant sperm immunogens have been observed to block sperm-egg interactions in vitro. Anti-fertility effects have been demonstrated in baboons inoculated with synthetic sperm peptides. Thus, the theoretical bases for the emergence of a contraceptive vaccine based upon recombinant proteins or synthetic peptides are at hand, and initial results have been promising.
In the field of structural biology the theory and modeling of protein-ligand interactions using X-ray and/or NMR structures provides an experimental foundation for the design of small molecule inhibitors. Defining the partners of particular proteins, the signaling networks in which a given protein participates, how tightly interacting proteins touch one another, the 3-D shape of catalytic pockets in enzymes, the surfaces by which proteins make contact, and molecular modeling software now allows medicinal chemists to predict chemical and physiological properties of a drug target and its potential ligands. Calculation of molecular mechanics, ligand- docking techniques using computer graphics, and the thermodynamics of ligand binding provide a "mechanism-based approach" to designing potential antagonists. Advances in chemical syntheses, particularly combinatorial chemistry, where starting chemicals are reacted in all possible combinations to yield a library of thousands of compounds, are providing large collections of new agents which may be screened in various bioassays using automated systems [high throughput screening] to efficiently select biologically active compounds and reliably distinguish real "hits" from "artifacts." The field of contraception is poised to apply the methods of mechanism based drug design to target proteins unique to gametogenesis.
The Center promotes its aims in the following specific ways:
1. The People. The Center has an administrative structure which integrates the activities of a number of seasoned, highly productive Principal Investigators in the field of gamete biology. This multi-institutional, interdisciplinary group of investigators has extensive experience in the molecular basis of spermatogenesis, oogenesis, capacitation and fertilization and in the evaluation of candidate proteins for contraceptive targeting. The Center strengthens their interrelationships and collaborations, oversees the quality of applied research, monitors the development of vaccine formulations, the screening of antagonists, and the testing of contraceptive candidates, and provides effective and reliable management of resources. In addition, outstanding leaders from industry, chemical engineering, reproductive biology, immunology, urology, and obstetrics and gynecology are assembled as members and advisors to the Center.
2. The Environment. Specialized Core units established within the Center for Research in Contraceptive and Reproductive Health provide shared access to specialized technical expertise and resources essential to the discovery and validation of gamete specific proteins and their development as contraceptive vaccines and as targets for the screening of contraceptive antagonists. Cores include resources to administer center activities, evaluate the specificity of gamete gene expression, express gamete proteins and purify recombinant proteins under good laboratory practices [GLP], assess the in vitro effects of antibodies to gamete antigens, knock out target genes, crystallize and study the 3-D structures of high priority contraceptive targets, and conduct small animal and primate testing in pre-clinical trials. The Center also accesses expertise and resources through collaborations with a variety of institutions and industry including other Centers supported by the Contraceptive and Reproductive Health Branch. In addition it is important to the eventual success of any new innovation that discoveries and inventions be monitored so that strong intellectual property positions are established through timely patenting. This fosters the transfer of technologies to industrial partners. Through the Center's environment, interdisciplinary exchange of intelligence between basic investigators, chemical engineers, clinicians, regulatory affairs personnel, and industry representatives is maximized in order to develop safe and effective products. Moreover, the environment of the Center is supportive of training and outreach missions by providing shared laboratory resources and expertise critical to the training and development of new investigators in disciplines required to master both basic research in the discovery of contraceptive targets and the applied realms of formulation and testing of recombinant and synthetic contraceptive vaccines and antagonists.
3. The Products. The Center focuses research and development efforts on promising contraceptive targets associated with human sperm. Sperm immunogens in the initial discovery phase, immunogens which have already been formulated and are undergoing primate trials, and peptide vaccines which are poised to enter Phase I human trials all are included in the scope of the Center's current activities. Strategies for developing peptide vaccines against the zona pellucida that separate immunopathological effects from contraceptive action are being evaluated in mice and monkeys. The Center also identifies for transfer into industry validated contraceptive target genes from the egg and sperm to permit drug discovery. As a result of basic research defining gamete specific antigens and genes, the Center has encouraged the development of new diagnostics for the field of male contraception and topical intra-vaginal spermicides. These include a patented immunodiagnostic test for sperm quantitation [SpermCheck] and a new spermicidal/spermistatic, RASA, based on a recombinant antibody to a reproductive tract specific sperm glycoprotein.
4. Education and Career Development of New Investigators. The Center has created an environment for the training of young scientists in the multi-disciplinary fields necessary to successfully identify, validate and evaluate new contraceptive targets for vaccines and antagonists. The Center trains young investigators to translate basic discovery into useful products, and it provides incentives for young scientists trained in ancillary fields to explore research opportunities in contraceptive development to cross-fertilize the field.
Patents, and products:
Patents Developed by CRGCV staff at the University of Virginia and Held by the UVA Patents Foundation:
1. Inventors: J.C. Herr, M. Sigman & W. Sutherland. Title: "MHS-5-A Novel Probe for Sexual Assault Analysis". U.S. Patent 4,741,998, granted May 3, 1988.
2. Inventors: J C. Herr, M. Sigman, W. Sutherland. Title: "Monoclonal Antibody to MHS-5; a New Probe for Sexual Assault Analysis". U.S. Patent 5,047,508, granted September 10, 1991.
3. Inventors: J.C. Herr, O. Benjamin & W. Sutherland. Title: "Monoclonal Antibody UVA-HSA-1 to a Unique Epitope on Human Serum Albumin: A Probe for Identification of the Human Origin of Blood or Tissue". U.S. Patent 4,735,898, granted April 5, 1988.
4. Inventors: J.C. Herr and R. M. Wright: "Human Intra-Acrosomal Sperm Antigen for Use in a Contraceptive Vaccine." Filed, Feb. 16, 1990. US Patent 5,436,157 granted July 25, 1995.
5. Inventors: J.C. Herr and R.M. Wright. "Primate Intra-acrosomal Sperm Antigen for Use in Contraceptive Vaccine." Filed: March 27, 1992 U.S. Patent 5,602,005 granted February 11, 1997.
6. Inventors: J.C. Herr and R.M. Wright. "Primate Intra-Acrosomal Sperm Antigen for Use in a Contraceptive Vaccine". U.S. Patent 5,753,231 granted May 18,1998.
7. Inventors: D. Gerdt and J.C. Herr. "Fiber Optic Evanescent Wave Sensor for Immuno- assay." US Patent #5,494,798, Granted Feb. 27, 1996.
8. Inventors: J. C. Herr and R. M. Wright. "Human Sperm Diagnostic." Filed: April 25, 1994 U.S. Patent 5,605,803, granted February 25, 1997.
9. Inventors: J.C. Herr, A.B. Diekman, and E. Norton. "Purified Sperm Surface Antigen, Monoclonal Antibody Therefor and Applications Therefor." U.S. Patent 5,830,472 granted November 3, 1998. U.S. Patent 6,258,364 granted July 10, 2001.
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