Mice born with a genetic defect that renders them infertile have given birth to litters of pups thanks to a gene-editing technique. Describing this incredible breakthrough in the journal Cell Reports Medicine, the researchers behind the experiment say their approach could one day be used to treat infertility in humans.
Premature ovarian failure, which occurs when the ovaries become unable to release hormones needed for egg production, is thought to affect about 1 percent of women by the age of 40. The condition depends on numerous molecules that regulate the crosstalk between oocytes and granulosa cells, which produce estrogen, progesterone, and other key hormones.
One such molecule, known as KITL, controls numerous stages of oocyte development, which is why people who harbor mutations in the gene that codes for this particular compound tend to suffer from fertility problems. Unfortunately, it is not possible to directly treat patients with KITL, since the impermeability of the blood-follicular barrier prevents uptake by the ovaries.
The study authors therefore used a type of virus called an adeno-associated virus (AAV) to introduce a gene for KITL production into female mice that lacked this key reproductive molecule. Considered the most promising viral vectors for gene therapy, AAVs can deliver macromolecules into cells through a process called transcytosis.
While the researchers expected to see an increase in KITL production within these infertile mice, they were somewhat surprised to find that the mice actually became capable of reproduction after treatment. Of the 19 mice involved in the experiment, eight produced pups after mating with a male, and one mother became pregnant again and gave birth to a second litter.
“The restoration of fertility by natural mating was unexpected,” the study authors write.
Importantly, all of the pups were completely normal and healthy, and no viral DNA was found in the pups. According to the researchers, “the lack of transgenic DNA in the offspring after direct ovarian injection suggests that AAV injection may be safe.”
“Despite the success of this work, efforts are still needed to increase transduction efficiency and fertility,” they say. “More than half of the injected mice remained infertile, and only one of the fertile mice was able to produce two litters.”
Long-term fertility testing will help confirm the safety and efficacy of the approach, but the authors are understandably excited about the implications of their findings to date. Overall, they conclude that “our results, albeit in mice, suggest that some cases of female infertility in humans can be treated by AAV-mediated gene therapy.”