mRNA therapy restores sperm production and fertility in mice

Osaka, Japan - For many couples facing infertility, medicine offers a range of solutions. But for men with non-obstructive azoospermia (NOA)—a genetic condition where sperm production stalls—options remain limited. Researchers at The University of Osaka in collaboration with Baylor College of Medicine have developed a pioneering approach to combat NOA. By delivering mRNA through lipid nanoparticles (LNPs) targeting specific testicular genes, they successfully restored sperm production and achieved the birth of viable offspring in a mouse model.  This treatment led to healthy, fertile offspring and pointed toward realistic, gene-informed therapies

Infertility affects one in six couples globally, with male factor infertility accounting for almost half of these cases. NOA, a condition characterized by the lack of sperm in the ejaculate despite normal hormonal levels, often stems from genetic defects disrupting spermatogenesis. Current treatments for NOA are limited, leaving thousands of affected individuals without viable options to conceive biologically.

This study focused on a NOA mouse model suffering from meiotic arrest due to a genetic deficiency. The team injected LNPs into the rete testis to fill seminiferous tubules and deliver mRNA broadly (Fig.1). Expression lasted ~5 days and reached ~55% of tubules. To bias expression to germ cells (not Sertoli cells), they appended the Dsc1 3’-UTR containing a miR-471 target, shifting translation away from Sertoli cells and toward germ cells (Fig. 2). In Pdha2 knockout mice—where meiosis arrests—the delivered Pdha2 mRNA resumed meiotic progression, yielding round spermatids by 2 weeks and sperm by 3 weeks. Using testicular sperm for ICSI produced 26 pups from 117 embryos (22.2%) (Fig. 3), which developed normally, were fertile, and showed no large (>1 Mb) genomic alterations.

This study offers a groundbreaking approach for treating male infertility caused by genetic defects. By restoring spermatogenesis in a non-obstructive azoospermia (NOA) mouse model using lipid nanoparticle (LNP)-mediated mRNA delivery, it introduces a safer, non-integrating alternative to traditional gene therapies, providing hope for untreatable infertility cases in humans.

Professor Masahito Ikawa, senior author of the study says, “Using fully synthetic LNPs to deliver mRNA minimizes genome-integration concerns and enables us to restore spermatogenesis in a defined genetic model. Professor Martin M. Matzuk also says, “These findings clarify how spermatogenesis can be rescued and lay the groundwork for applied research toward treating certain forms of male infertility.”

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The article, “Sperm and offspring production in a non-obstructive azoospermia mouse model via testicular mRNA delivery using lipid nanoparticles,” will be published in Proceedings of the National Academy of Sciences at DOI: https://doi.org/10.1073/pnas.2516573122.

About The University of Osaka

The University of Osaka was founded in 1931 as one of the seven imperial universities of Japan and is now one of Japan's leading comprehensive universities with a broad disciplinary spectrum. This strength is coupled with a singular drive for innovation that extends throughout the scientific process, from fundamental research to the creation of applied technology with positive economic impacts. Its commitment to innovation has been recognized in Japan and around the world. Now, The University of Osaka is leveraging its role as a Designated National University Corporation selected by the Ministry of Education, Culture, Sports, Science and Technology to contribute to innovation for human welfare, sustainable development of society, and social transformation.

Website: https://resou.osaka-u.ac.jp/en