Human induced pluripotent stem cells (hiPSCs) show great promise in the development of novel strategies to mitigate reproductive diseases and promote successful reproductive outcomes. Recently, a novel approach for the fast and efficient differentiation of ovarian support cells (OSCs) to generate a versatile platform for basic research and clinical applications was demonstrated. This study details the clinical process development and application of an OSC product, known as Fertilo, to improve the in vitro maturation (IVM) of human oocytes, a method referred to as OSC-IVM. First, transcription factor (TF) mediated OSC differentiation using research-grade raw materials was shown to produce granulosa-like cells that improve the MII maturation rate of human oocytes. To support clinical application, several raw material upgrades were initiated, including substitution of the differentiation matrix with a higher-quality alternative, laminin-521, and the generation of a clinically suitable hiPSC seed bank and master cell bank. Single cell RNA sequencing of OSCs generated using the updated protocol for clinical translation demonstrated the consistency and reproducibility of cellular outcomes. Next, analytical release testing of the clinical product was performed and a murine oocyte maturation assay was developed to establish the potency of OSCs for use in OSC-IVM. Finally, the qualified Fertilo product was applied in a two-phase longitudinal cohort analysis, with the results showing improvement in key outcomes compared to traditional IVM treatment. Our findings demonstrate the first-time clinical development and application of an hiPSC-derived product to improve reproductive outcomes after IVM and advance women’s health.

B.P., F.B., A.D.N., M.J., S.K., S.P., M.M., A.B.F., C.L., P.B., and C.C.K. are/were shareholders in the for-profit biotechnology company Gameto Inc while performing this work. C.C.K., S.P., M.M., B.P., and A.D.N. are listed on a patent covering the use of OSCs for IVM: U.S. Provisional Patent Application No. 63/492,210. Additionally, C.C.K. is listed on three patents covering the use of OSCs for IVM: U.S. Patent Application No. 17/846,725, U.S Patent Application No. 17/846,845, and International Patent Application No.: PCT/US2023/026012. C.C.K., is listed on three patents for the TF-directed production of granulosa-like cells from stem cells: International Patent Application No.: PCT/US2023/065140, U.S. Provisional Application No. 63/326,640, and U.S. Provisional Application No. 63/444,108.

ISRCTN36032472

https://www.isrctn.com/ISRCTN36032472

This work was funded by the for-profit biotechnology company Gameto Inc.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Ethics committee of the Universidad Peruana Cayetano Heredia, Protocol Fertilo P1, approved by the ethics committee (CIEI-FMH-USMP, FWA No. 00015320, IRB No. 00003251)

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