According to a new Stem Cell Reports paper, scientists have demonstrated that targeted delivery of mRNA can restore sperm production and fertility in genetically infertile male mice without introducing permanent changes to the germline. Full details are provided in a paper titled “Messenger RNA delivery into Sertoli cells restores fertility to congenitally infertile male mice.” The study was done by a team of scientists from Kyoto University, RIKEN, and elsewhere.
The findings represent a step forward in efforts to develop therapies that may help people affected by infertility. According to estimates from the World Health Organization, up to 10 percent of couples worldwide are affected by infertility. In about half of those cases, male factors are the primary cause. As noted in the paper, “male infertility often results from impaired interactions between germ cells and Sertoli cells.” Furthermore, methods like in vitro fertilization and intracytoplasmic sperm injection “are applicable in many cases; however, these techniques are useful only when haploid gametes are available,” they wrote.
To develop a targeted method that could address genetic defects, Takashi Shinohara, MD, PhD, a professor in the department of molecular genetics at Kyoto University, and his team injected mRNA into mice testes. The team first confirmed that this approach successfully delivered the genetic material to the sperm-producing cells and supporting Sertoli cells in the testis. They then tested whether mRNA delivery could restore fertility in male mice carrying a specific genetic defect in Sertoli cells that blocks sperm production. This defect has also been implicated in human infertility and testicular disorders.
“We chose to employ mRNA delivery to Sertoli cells for several reasons. First, the testes are considered immune-privileged organs, and thus we anticipated that potential immunostimulatory nature of mRNA would be minimized within the testes due to the modulatory effects of Sertoli cells on innate and adaptive immunity,” the team explained in the paper. “Second, the testes are anatomically enclosed in a tight collagen sac, comprising closed interstitial tissue and semi-closed seminiferous tubules. This anatomical feature would help maintain relatively high concentrations of mRNA within the injected space, unlike injection into the bloodstream…. Third, the absence of differentiated germ cells in infertile testes facilitates direct incorporation of mRNA into Sertoli cells.”
Introducing the therapy did trigger an innate immune response, however the results showed that delivering the mRNA to the testis was enough to unlock spermatogenesis in the genetically infertile mice. Specifically, “delivery of naked Cldn11 mRNA into Cldn11-deficient mice, which have meiotic defects due to defective blood-testis barrier, allowed progression from spermatocytes to spermatids” with no “major side effects,” the scientists wrote. Importantly, sperm collected from treated animals generated healthy pups when injected into mouse oocytes by in vitro fertilization.
Though the results are promising, it’s still too early to test the treatment in humans. Additional studies in animal models are needed to further evaluate the safety and efficacy before considering potential clinical applications in human patients.
