Development of Superactive Analogs of FSH

FSH 超活性类似物的开发

• 批准号: 7054432
• 负责人: Bruce Dale Weintraub
• 金额: $ 60.12万
• 依托单位: TROPHOGEN, INC.
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-03-15 至 2008-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7054432
• 关键词: Primates; SDS polyacrylamide gel electrophoresis; age difference; animal old age; bioreactors; cell line; drug discovery /isolation; egg /ovum; exo alpha sialidase; fertility; follicle stimulating hormone; high performance liquid chromatography; hormone analog; in vitro fertilization; juvenile animal; laboratory mouse; laboratory rat; mature animal; protein purification; protein quantitation /detection; reproductive development

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：不孕症影响着大约 10% 的美国夫妇，该领域的治疗市场非常大且增长迅速，特别是负责卵巢卵母细胞发育的主要激素——卵泡刺激素 (FSH)。尽管现有的泌尿和重组 FSH 产品已相当成功，但目前对于所有不孕妇女，特别是老年患者和对当前疗法相对无反应的患者，对改进的 FSH 类似物的治疗需求尚未得到满足。我们之前已经描述了第一个超活性糖蛋白激素类似物，可显着提高受体结合亲和力以及体外和体内生物效力和最大功效。在 Trophogen, Inc. 的第一阶段支持期间，我们在多个体外和体内模型中确定了许多有前途的 LH 和 FSH 超活性类似物候选物，包括啮齿动物卵母细胞的数量和质量。现在，我们希望在第二阶段的支持下，集中精力在各种生理和治疗相关的啮齿动物和非人类灵长类动物模型中，对我们的主要 hFSH 类似物候选物和两种替代品与标准重组 FSH 进行进一步的体内测试。具体来说，在啮齿动物中，我们建议采用经典的 Steelman Pohley 测定、体外受精和胚胎发育的各种测定，以及在选定的情况下，将胚胎移植到代孕雌性，评估妊娠率以及新生幼崽的数量和质量。此类研究将在未成熟、成熟和衰老的啮齿动物以及具有遗传或化学诱导不育模型的啮齿动物中进行。在非人类灵长类动物中，我们建议使用模拟人类 ART 的方法对模拟与标准 FSH 进行配对研究。我们还建议使用主要的 FSH 类似物候选物开发更多稳定的细胞系，并进一步优化纤维床生物反应器的生产以及纯化方法。此外，我们计划通过与蛋白质和碳水化合物结构相关的多种物理化学方法来表征选定的纯化类似物。