An international team of researchers, led by Baylor College of Medicine and the University of Osaka, has developed a new method to restore sperm production in mouse models with non-obstructive azoospermia (NOA). NOA is a condition where men are infertile due to the inability to produce sperm, often because of genetic defects affecting the process of meiosis, a crucial cell division step in sperm development.
The study, published in Proceedings of the National Academy of Sciences, explored the role of the gene PDHA2, which is essential for meiosis. In cases where this gene is defective, men are unable to produce mature sperm. Current treatments such as surgical sperm retrieval or hormonal therapy are not effective if no mature sperm are present.
The research team, led by Dr. Daisuke Mashiko and Dr. Masato Ikawa from the University of Osaka and Dr. Martin Matzuk from Baylor College of Medicine, used a lipid nanoparticle (LNP)-based method to deliver Phda2 mRNA to the affected cells in a mouse model. This approach does not change the DNA but bypasses the genetic mutation by providing the necessary PDHA2 protein directly to immature sperm cells.
To target only sperm-producing cells, the researchers included miRNA target sequences to ensure the PDHA2 protein was expressed only in the male germline. Once the protein was restored, normal meiosis resumed, and mature sperm were produced.
Following treatment, the researchers observed that the treated mouse models produced functional sperm and went on to have healthy offspring. Whole-genome sequencing confirmed that the offspring did not have large-scale genomic abnormalities.
Dr. Martin Matzuk said, "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." He added, "These international collaborative studies were initiated a decade ago through Osaka University's International Collaborative Research Promotion Program between Professor Ikawa’s team at Osaka University and my research group at Baylor College of Medicine in Houston, Texas."
The research included contributions from Chihiro Emoria, Yuki Hatanakaa, Daisuke Motookaa, Chen Pana, and Yuki Kanedaa from the University of Osaka, the University of Tokyo, and Baylor College of Medicine. The project received funding from several Japanese agencies as well as the Eunice Kennedy Shriver National Institute of Child Health and Human Development and a master plan implementation project at the University of Osaka.
