McGill Researchers Have Found A Possible Path For Treatment of Fragile X Syndrome

There is no denying autism spectrum disorders, commonly known as ASD, have become some of the world’s greatest health concerns. But what most people do not know is the incredible complexity of these conditions. As researchers have found, the problems are not singular in nature. Rather, they are a consequence of several changes in the way the cells of the brain function. This reality has forced ASD researchers to head deep into the molecular level of the brain in the hope of understanding what is happening in those affected.


As one might expect, the work is painstaking and requires years, if not decades, of intense study with results sometimes only representing baby steps towards our understanding of this ailment. Yet there are times, however, when a discovery is made that takes a stream research into a brand new direction. One perfect example of this happened in the 1960s.

As It started when a group of doctors uncovered a connection between a genetic mutation and developmental disabilities in male children of a family. Researchers investigated the cause of this disability and came across a landmark finding. The mutation could be mapped to the X chromosome. Perhaps even more fascinating was the realization that the mutation appeared to be similar in several individuals with this disability.

The ball was rolling and soon, the specific site of the mutation was known. Officially, it was called Xq27.3, which is where a gene known as FMR1 is encoded. But for most people, it became known as the Fragile X locus. As more cases of this syndrome were collected and genetic analyses found the same link to this region, there was little doubt of the cause-effect link. Eventually, the condition became known as Fragile X Syndrome, or FXS.  Besides intellectual disability, more recently, FXS was officially linked to ASD, appearing in about 50-60% of people with FXS.

This twenty-year journey was pivotal for autism research. Yet, there was still one problem. While one of many causes had been found, there was no means to develop therapies. More time, resources, and research would be needed to gain a greater understanding of the impact of FXS and how to treat it.
In the thirty-five years that have passed, FXS has been the focus of research worldwide and has opened the door to a wide variety of researchers. One such researcher is Dr. Nahum Sonenberg. His team at McGill University has been focusing on the cellular mechanisms in health and disease for decades.

In 2014,  his team linked the aberrant production of cellular proteins to FXS. They found the FXS mutation disrupted normal brain activity by altering the way the neuronal cells functioned. It was not a simple matter of blocking or interference, however. This was a systemic change to the way the cells behaved. It took time to sort out all the details but eventually, the Sonenberg group, together with other researchers, managed to find a molecular culprit.

It is known as hyperactivation of extracellular signal-related kinase or ERK. When FXS occurs, the levels of the active form of this protein are increased and cells become hyperactive in nature. This alteration of the cell’s function leads to the imbalance of certain proteins necessary for proper brain function. The end result is a lack of proper brain activity and the ensuing effects of FXS.

For Sonenberg’s team, this offered some good news. Since one of the mechanism behind this inbalance was due to ERK, there were possible means to treat it using specific drugs targeting this pathway. If they were right, they could start a new branch of research in which the goal would not be understanding, but rather treating FXS.
After years of work, the team has finally opened that door to therapy. They have published in the journal Nature Medicine their findings on a new drug to treating a mouse model of FXS. Surprisingly, the therapeutic is not some new chemical or lab creation but one that has been around for years, metformin.

The idea of the team’s work was based on how metformin works. It reduces the energy state of the cell such that it cannot be hyperactive. For the team, this was the perfect choice for a treatment candidate. By slowing down the cell at the molecular level, it may be triggered back to normal acting levels .
The experiments were straightforward. Either metformin or a control solution was injected into the abdominal area of mice possessing the FXS mutation. This occurred once a day for ten days. After the last injection, the mice were examined for any signs of behavioural change. In addition, cellular observations were made to determine if any changes in the brain could be reversed.

The results left little doubt. Metformin had done the job just as expected. Several mouse behaviours improved as did their brain cells. The team had found – at least in mice – a possible treatment for autism-like behaviour in fragile X syndrome.

Much like the discovery of the fragile X chromosome back in the 1960s, the group’s results are a milestone that takes us to a new realm of study. Yet, as with that discovery over fifty years earlier, this is just the start of the journey. More studies in animals are needed to confirm these results and demonstrate the treatment works in more than just mice.
It will take years to get us to the next big step – clinical trials – but the research is moving quickly. Earlier this year, a small study involving testing metformin in 7 FXS patients has given us a good indication of the treatment possibilities of metformin. Thanks to the work of Sonenberg’s group and others over the decades, we can move forward optimistically knowing we have a possible means to treat one of the most troublesome diseases of our time.

Original research article:

Gantois I, Khoutorsky A, Popic J, Aguilar-Valles A, Freemantle E, Cao R, Sharma V, Pooters T, Nagpal A, Skalecka A, Truong VT, Wiebe S, Groves IA, Jafarnejad SM, Chapat C, McCullagh EA, Gamache K, Nader K, Lacaille JC, Gkogkas CG, Sonenberg N. Metformin ameliorates core deficits in a mouse model of fragile
X syndrome. Nat Med. 2017 Jun;23(6):674-677. doi: 10.1038/nm.4335. Epub 2017 May 15.