Reproducible and Scalable Differentiation of Ovarian Support Cells from a Clinical-Grade hiPSC Line to be Applied as a Novel in Vitro Maturation Strategy for Infertility Treatment

In vitro maturation (IVM) is an assisted reproductive technology in which immature oocytes are retrieved with abbreviated stimulation and matured outside the body, offering a safer alternative to generate mature eggs for infertility treatment. Despite the clear benefits to the patient, when compared with conventional protocols, IVM yields in general less usable mature oocytes, limiting its utilization as standard of care. We recently demonstrated that ovarian support cells (OSCs) derived from hiPSCs in co-culture with immature human oocytes mimic the ovarian environment allowing for higher rates of oocyte maturation and euploid embryo formation, offering a novel solution to overcome the limited yield in IVM. Translating novel cell-based IVM products to clinics however represents certain challenges beyond efficacy, namely manufacturing at scale, integration of commercial-grade raw materials, and ensuring purity, reproducibility, and safety. As we translate this technology towards clinical manufacturing and application, we optimized our manufacturing protocol
to deliver increased scale and substituted raw materials with appropriate animal origin-free alternatives, which included a systematic methodology to select an ideal substrate. These modifications improved the efficiency, purity, and consistency of the differentiated OSC population, ultimately improving consistency of functional outcomes. Most importantly, we sourced a compliant female clinical/commercial-grade hiPSC line as starting material, and operated in controlled environments to create a new cell line by applying an identical engineering strategy to originally create the research-use-only (RUO) hiPSC line. OSCs differentiated from the new hiPSC line delivered similar quality attributes and clinical outcomes previously demonstrated with our RUO line, with an increase in consistency and reproducibility across batches. This technology is currently being applied in a first-in-human OSC-IVM observational study with reported pregnancies. Overall, we have demonstrated
that our strategic approach to product development meets scalable manufacturing needs and ultimately supported a product of improved efficacy, quality, and safety. Protocol: Amended Protocol Fertilo P1 v05, (Oficio No. 142 -2024- CIEI-FMH-USMP), Clinical Trial Registry: ISRCTN36032472.