Infertility affects about 10% of American couples, and there is a very large and rapidly growing market for therapeutics in this field, particularly the primary hormone responsible for ovarian oocyte development, follicle-stimulating hormone (FSH). Although available urinary and recombinant FSH products have been quite successful, there is currently an unmet therapeutic need for improved FSH analogs for all infertile women and particularly for older patients and those relatively unresponsive to current therapies. We have previously described the first superactive analogs of glycoprotein hormones that considerably increase receptor binding affinity as well as both in vitro and in vivo biopotency and maximal efficacy. During our Phase I support at Trophogen, Inc. we have identified a number of promising LH and FSH superactive analog candidates in several in vitro and in vivo models, including rodent oocyte quantity and quality. We now wish under Phase II support to focus our efforts on further in vivo testing of our lead hFSH analog candidate and two alternates versus standard recombinant FSH in various physiologically and therapeutically relevant rodent and nonhuman primate models. Specifically, in rodents we propose to employ the classic Steelman Pohley assay, various assays of in vitro fertilization and embryo development and, in selected cases, embryo transfer to surrogate females, assessment of pregnancy rates and the quantity and quality of newborn pups. Such studies will be performed in immature, mature and aging rodents as well as in those with models of genetic or chemically induced infertility. In nonhuman primates we propose to do a paired study of analog vs standard FSH using methods emulating human ART. We also propose to develop additional stable cell lines with the lead FSH analog candidates and optimize further fibrous bed bioreactor production as well as purification methods. In addition we plan to characterize selected purified analogs by multiple physicochemical methods relating to both protein and carbohydrate structure. ? ?
