Protein supply to the testes restores male fertility in mice

About 15% of couples are infertile, and male infertility plays a role in over a third of those cases, according to the Mayo Clinic. Problems with sperm development are often to blame. Now researchers, reporting in ACS Nano, have found a way to deliver a protein important for sperm cell production directly to mouse testes, where it restored normal sperm development and allowed previously infertile mice to father puppies.

Male infertility often occurs due to a lack of sperm in the semen, which can result from damage to the blood-testicular barrier (BTB). This barrier protects the reproductive cells from harmful toxins and drugs, and a protein called PIN1 is important for its function. Mice that have been genetically engineered to lack PIN1 are sterile, with small testes, depleted sperm stem cells, and low sperm counts.

Although scientists have considered gene therapies to treat male infertility, these procedures are risky because they can cause undesirable genetic changes in reproductive cells that may be passed on to offspring. Hyun-Mo Ryoo and colleagues wanted to develop a system to deliver proteins (like PIN1) to the testes instead of genes, but first they had to find a way to get proteins into cells through the complex tubes of the testes .

The researchers developed a delivery system called Fibroplex, which consisted of spherical nanoparticles made from silk fibroin and a lipid coating. They loaded PIN1 into Fibroplex and showed that the particles appeared safe and showed no signs of toxicity or testicular damage in mice. When the team injected the PIN1-laden fibroplex with PIN1 deletions into the testes of young mice, the treatment restored near-normal PIN1 levels and sperm stem cell counts, and repaired the BTB.

Treated mice had normal testis weight and size and about 50% of the sperm count of wild-type mice. Until about 5 months after treatment, when the protein was degraded, the PIN1-Fibroplex treated mice produced similar numbers of pups to wild-type mice, while untreated mice with PIN1 deletions remained sterile. This is the first evidence of direct delivery of proteins in the testes for the treatment of male infertility, the researchers say.

Source:

American Chemical Society

Journal reference:

Kim, WJ, et al. (2020) Intratesticular Peptidyl Prolyl Isomerase 1 Protein Delivery Using Cationic Lipid-Coated Fibroin Nanoparticle Complexes Rescues Male Infertility in Mice. ACS Nano. doi.org/10.1021/acsnano.0c04936.

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