The long-term goal of this proposal is to develop a safe, effective and user-friendly vitrification system for cryopreservation of whole human ovaries. In the U.S., over 140,000 girls and women age 0-49 are diagnosed with cancer annually. While improved diagnosis and treatment have led to increased survival rates (75% in premenopausal and 85% in childhood cancer patients), devastating side effects of cancer therapies include premature ovarian failure, infertility and menopause-related health risks. While cryopreservation of embryos and oocytes are effective, ovarian cortex and whole ovary cryopreservation is the only option for future fertility in prepubertal patients and those who require immediate cancer treatment. Cryopreservation of whole ovaries, compared to ovarian tissue, has added advantages of 1) preserving all classes of follicles, which can be used for in vitro maturation, 2) longer graft lifespan, and 3) faster recovery supported by existing blood vessels after transplantation with vascular anastomosis. However, current methods for whole ovary cryopreservation are suboptimal and there is no technology designed for cryopreserving human ovaries, despite it being the best choice for prepubertal cancer patients for future fertility and intact endocrine function for decades without the help of exogenous hormones. The proposed research is part of 21st Century Medicines more general program of developing superior organ cryopreservation systems, including cryoprotective agent (CPA) solutions, perfusion apparatus (hardware and software) for CPA loading and unloading, and liquid nitrogen storage units. This Phase II will help us initiate our effort in achieving our ultimate goal as an organ banking company. Our company has successfully demonstrated functional preservation of vitrified rabbit kidneys after transplantation. In this SBIR Phase II study, we will validate and continue improving our success thus far in whole ovary vitrification using large animal models of ovary transplantation in pigs and sheep (sheep has an established ovary transplant procedure and their ovarian structure is closer to the human than the pig). We will also develop a nonhuman primate preclinical model for ovary transplantation as well as characterize the cryogenic properties of monkey ovaries. Furthermore, we will finalize the Ovary Perfusion Device and develop a closed system for storing individual cryopreserved ovaries for eventual clinical use. The resultant technology of this Phase II project will be the first perfusion unit designed for the human ovary and can simultaneously control temperature, pressure, flow rate and CPA concentration with a build-in feedback mechanism to maintain constant pressure during perfusion. Upon successful completion of Phase II, we will submit a Phase IIb application to include fertility trials using the nonhuman primate model, human tissue xenografting experiments, and finalizing strategies for commercialization. This novel system will offer new hope to the thousands of cancer survivors and the impact could be significant and sustained.
Public Health Relevance Statement: PROJECT NARRATIVE One devastating side effect of cancer treatment is premature ovarian failure which can lead to infertility and long term health risks associated with menopause. Compared to existing fertility preservation methods (embryo, oocyte and ovarian tissue cryopreservation), whole ovary cryopreservation offers complete recovery of ovarian function (endocrine and fertility), which is important for young, especially prepubertal, cancer patients. Currently, technology for cryopreservation of whole human ovaries does not exist; therefore, the overall objective for this SBIR project is to develop a safe, effective and user-friendly cryopreservation system for human ovaries.
Project Terms: Adolescent; Age; Aluminum; Anastomosis - action; Animal Model; Antral; Blood; Blood flow; Blood Vessels; Cancer Patient; Cancer Survivor; cancer therapy; Cell Proliferation; Childhood; Clinical; commercialization; Computer software; Cortex of ovary; cost; cryogenics; Cryopreservation; Cryoprotective Agents; design; Devices; Diagnosis; Diagnostic; Disease; Early Diagnosis; Embryo; embryo cryopreservation; Endocrine; Engineering; Estradiol; Evaluation; experience; experimental study; Family suidae; Feedback; Female; Fertility; fertility preservation; Freezing; Future; girls; Goals; Health; Histology; Hormones; Human; human tissue; Ice; improved; In Vitro; in vivo; Individual; Infertility; ischemic injury; Kidney; Lead; Life; Liquid substance; Live Birth; Longevity; Macaca mulatta; Malignant Childhood Neoplasm; Malignant Neoplasms; Measures; Medicine; Menopause; Methods; Modeling; Monkeys; Nitrogen; nonhuman primate; novel; oocyte cryopreservation; Oocytes; Organ; Oryctolagus cuniculus; Osmotic Shocks; Ovarian; Ovarian Tissue; Ovarian tissue cryopreservation; Ovary; ovary transplantation; Partner in relationship; Patients; Penetration; Perfusion; Phase; phase 2 study; Polypropylenes; portability; Pre-Clinical Model; Pregnancy Rate; Premature Ovarian Failure; Premenopause; Preparation; prepuberty; preservation; pressure; Procedures; Production; Progesterone; programs; Property; Protocols documentation; prototype; Recovery; Reporting; reproductive; Research; Research Personnel; Risk; Safety; Sampling; Serum; Sheep; side effect; Slice; Small Business Innovation Research Grant; Specimen; Structure; success; Surgeon; Survival Rate; Survivors; System; Techniques; Technology; Temperature; Tissues; tool; Toxic effect; Transplantation; Treatment Protocols; Ultrasonography; user-friendly; Vial device; Woman; Xenograft procedure
