Lowering the BMI can improve older men's fertility


	View in browser

Gene therapy cures infertility in female mice

3-min Science Digest · 13 September 2022

In 10 seconds? Scientists have used gene therapy to fix an abnormal cell function causing infertility. They have targeted granulosa cells that regulate the development of oocytes (eggs) in ovaries.

What’s the breakthrough about? It's about restoring fertility in females rather than making people resort to assisted reproduction therapy. One of the causes of female infertility is impaired ovulation. Researchers have managed to ‘repair’ faulty communication between defective cells in the ovaries that blocks ovulation or oogenesis, to use a sciency word… but it's early days as they achieved this in lab mice.

“Gene therapy”… can I get some clarity on this? In (very) simple words, gene therapy is a medical approach that treats or prevents, diseases by gene transfer. Both the EMA (the European Medicines Agency) and the FDA (the US Food and Drug Administration) define gene therapy as a biological medicinal product. This could be a free nucleic acid, viruses, or genetically engineered microorganisms. This new genetic material is inserted in some target cells, through different techniques, to solve particular problems.

So, how did they do it? They used genetically modified mice that don’t produce a particular protein. The protein in question plays an important role in the communication between ovary cells (in this case, the oocyte and the granulosa cells), and in fostering ovarian follicles development. Basically, they’ve created female mice with abnormal oogenesis. The goal of this experiment was to figure out a delivery mechanism to reach the granulosa cells and insert a functional copy of the therapeutic molecule.

Were the researchers successful with the mice? Yes! It was hard because granulosa cells are protected by a shield that prevents harmful substances in the blood to reach the oocyte. So, the team had to find a way to penetrate this barrier. And they did it! They found that a special type of virus (called adeno-associated viruses, AAV) could penetrate this barrier and deliver the therapeutic gene into the nucleus of the cells. In fact, they didn’t just succeed to deliver the therapeutic gene and rescue the damaged granulosa cells but those mice went on to have healthy offspring!

AAV-mediated gene delivery into ovaries for restoration of oogenesis in congenitally infertile mice. Source: Kanatsu-Shinohara, Lee, Miyazaki, et al, 2022.

And is this method safe? Yes! There is a lot of evidence that demonstrates this.During the last 10 years, a significant clinical benefit for regulatory approval to license gene therapy has been accumulated. Medical success has been demonstrated in disorders like primary immunodeficiencies and hemophilia. But the major clinical gene transfer experience (and success) has been in patients with cancer. Up to 2013, cancer was by far the most common group of diseases treated by gene therapy, with 60% of all ongoing clinical gene therapy trials worldwide, followed by cardiovascular diseases.

So, if this therapy is a common procedure, why this new research is important? First, so far, there had been only a few attempts to restore female fertility via gene therapy. You must also know that infertility has increased in the last few years. Only in the U.S., 12.2% of women aged 15-49 have used infertility services up to 2021. Globally – according to the WHO – infertility touches 48 million couples and 186 million individuals. Female infertility has many causes, but the most common is the abnormal function of the ovaries. Cell communication among cells in the ovaries is critical, so investigating this topic is important to develop new techniques or treatments.

Great, it works in mice but how is that relevant to people? Well, the most important information about this work is that shows that this type of therapy works by penetrating the ovary barrier and reaching the oocyte to restore its function. However, there are limitations before their use in humans. First, the authors have to explain the complete mechanism for fertility restoration, and then improve the efficiency of this potential treatment. To do all of this, other experiments will have to carried out using mice, and other mammals models, different types of this particular virus. Long-term fertility tests also need to be performed before humans trials.

Has there been any clinically successful cases?

Yes! Gene therapy using AAV is a safe and effective medical technique. Although, many treatments are under clinical trials, to date there are six gene therapies approved worldwide, of which three were created by modification of AAV.

One of the most important approaches of this study is the implementation of AAV gene therapy in fertility, and this is why the authors are confident that this could someday lead to new infertility treatments for humans as well.