mRNA treatment helps mice with azoospermia to regain fertility

A new mRNA-based therapy has restored fertility in mice that were unable to produce sperm.

Non-obstructive azoospermia (NOA) is where sperm are absent from semen due to failed production rather than a physical blockage. Researchers at Osaka University in Japan and Baylor College of Medicine in Texas were able to deliver messenger RNA (mRNA) in liquid nanoparticles (LNP) directly into the testes of mice genetically unable to produce sperm. The animals were then able to generate viable sperm and produce healthy offspring.

'Our exciting results provide proof of concept for a safe and effective LNP-based mRNA therapy, offering a promising strategy to treat male infertility caused by spermatogenesis arrest,' said Professor Martin Matzuk from Baylor, co-author of the study published in PNAS.

NOA affects around one percent of men and remains one of the most challenging forms of male infertility to treat. Current options are limited, and surgical sperm retrieval often fails when no mature sperm cells are present.

The study focused on mice lacking the gene Pdha2, which is essential for completing meiosis, the cell division process that produces mature sperm. Without this gene, sperm cells cannot develop properly, resulting in infertility. By injecting synthetic Pdha2 mRNA packaged in LNPs into the testes, researchers were able to replace the missing gene's function.

Within three weeks, treated mice began producing mature sperm. Using intracytoplasmic sperm injection (ICSI), 117 embryos were produced, and 26 healthy pups were born. The offspring were fertile and showed no detectable genetic abnormalities.

The mRNA remained active in the testes for several days but did not integrate into the animals' DNA, sidestepping potential off-target effects that can occur as a result of making changes to the genome.

'Using fully synthetic LNPs to deliver mRNA minimises genome-integration concerns and enables us to restore spermatogenesis in a defined genetic model,' said senior author Professor Masahito Ikawa, from Osaka University.

While the findings are promising, the researchers emphasised that the work is still at an early stage. Further studies will be needed to refine delivery methods and identify which genetic causes of NOA could be treated using this approach.