While most male infertility can be overcome by in vitro fertilization-intracytoplasmic sperm injection where sperm are injected directly into oocytes for fertilization, males who lack sperm production, such as many pediatric cancer survivors, cannot utilize this therapy since they do not produce sperm even as an adult due to their cancer therapy.

This is particularly relevant since the forward progress among our oncology colleagues in effectively treating cancers through combinations of targeted therapies has resulted in an estimated 83% survival among all boys diagnosed with cancer aged less than 15.¹ However, many of these therapies inflict significant and often irreversible gonadal damage. Specifically, germ cells (ie, spermatogonial stem cells) are particularly sensitive to chemotherapy and radiation therapy, and azoospermia rates may range between 19% and 97% of cancer survivors.^2,3 These numbers are concerning since 75% of male childhood cancer survivors will report desiring to father children of their own in the future,⁴ and sperm cryopreservation from ejaculated samples is not possible for pre-pubertal boys since spermatogenesis has not begun prior to puberty. However, spermatogonial stem cells populate the testis in prepubertal boys; thus, fertility preservation strategies are limited to testis biopsies and subsequent cryopreservation with hopes of the future development of a technology to regenerate spermatogenesis. In a recent study, most respondents were in favor of undertaking experimental interventions in hopes of preserving fertility despite the risks of complications, costs of banking tissue, and chance of new technological advances.⁵ Unfortunately, to date, no regenerative approaches for inducing sperm production in humans have been repeatedly successful, despite encouraging success in animal models.

To address this, our RegenerAIT (Regenerative and Advanced Infertility Therapeutics) program aims to help these males with nonobstructive azoospermia with no detectable sperm in the semen or with microdissection testicular sperm extraction. To accomplish this, we have constructed a highly interdisciplinary team of clinicians, biologists, computational biologists, and engineers to develop the technologies and processes working toward in vitro spermatogenesis. In our project recently supported by the AUA Rising Stars Competition, we will be integrating several levels of technology and experimentation. We will be using computational analyses of single-cell RNA sequencing data from human testis tissue to understand the somatic environment that coordinates the temporal and spatial regulation of human spermatogenesis in vivo, as well as the transcriptional events contributing to germ cell differentiation. These findings will subsequently be tested on human 3D organoids and 3D bioprinted tubules to assess function and impact on germ cell differentiation. Collectively, these technologies will integrate into a precision medicine pipeline aimed toward regenerating sperm production in vitro to be subsequently coupled to existing clinical workflows such as in vitro fertilization-intracytoplasmic sperm injection.

It has been an honor to receive this award and I am extremely grateful for the opportunity, support of my mentors, colleagues, and collaborators. It will be extremely helpful in supporting my career to dedicate additional time performing translational research activities relevant to this project that aims to develop novel therapies for males with nonobstructive azoospermia.