Your lab has recently received grants from the Spanish FINRett Foundation and the American International Rett Syndrome Foundation to develop new research on Rett syndrome. How do you value this support?

We really appreciate all the support we receive to carry out our research, but it has a very important added value when it comes from a foundation like FINRett, comprised of families of patients who throughout the year organize events to raise money and we know the effort behind it. The same can be said of the American Rett Syndrome Foundation, in which the contribution of the families is also decisive, even though in the United States we know there is an important tradition of support from philanthropists.

It is a firm commitment to research, isn't it?

Yes, these grants will help us in basic aspects of Rett syndrome and, although they have a clear therapeutic aspect, they will benefit patients in the future. They are very aware of this and, therefore, we do not only appreciate their support but we are also aware that we have an important responsibility to live up to the trust they place in us.

Let’s put some context, what can you tell us about Rett syndrome?

Well, it affects one in 10,000 newborn girls and that it is a particularly cruel disease, as it manifests itself between the first and second year of life as a slowdown of development and a progressive loss of communication and motor skills, often accompanied by respiratory defects and also epilepsy, without any previous evidence.

There’s no previous evidence? It must be a very hard moment for the families.

That's right, the diagnosis comes with the onset of symptoms, usually by a neuropediatrician who orders a genetic test. The lack of warning signs during the first months of life has a great impact both for girls and for the families who care for them. Despite being considered a rare disease, it is the second cause of Intellectual disability in girls after Down syndrome.

And what is the ultimate cause of the disease?

The ultimate cause is the alteration of the MECP2 gene, a general regulator of the activity of a multitude of other genes, especially in neurons, which prevents their correct maturation. We still do not know well enough the mechanisms that cause the specific symptomatology, since the action of MeCP2 is very broad, it does many things, and we do not know them all.

We know that minority diseases or syndromes do not often receive the attention they deserve. Could you tell us about the current state of research into Rett syndrome?

Research for the treatment of Rett syndrome is making progresses, but it is still a bet on the future and is closely linked to the development of gene therapy, since it is a genetic disease. Some years ago, we could see that the reintroduction of the corrected gene could reverse the symptoms in mouse models, even in adult animals. Of course, this does not imply that it also happens in humans, but in recent years important advances have been made in this regard. In addition, there are some drugs to treat the symptoms, such as apneas or epilepsies, but there is nothing specific for the Rett syndrome.

The revival of gene therapy, 20 years later!

Yes, absolutely! But gene therapy in Rett has two major problems: the first is that it is necessary to reach the affected cells. Therefore, we have to develop effective vehicles that can reach the brain tissue without generating as much toxicity as the current modified adenoviruses. The second problem to be solved is how to control the amount of MeCP2 once the gene is reintroduced. This is critical since excess protein produces a disease that is also quite severe.

We need to be careful then, how do you face this in your lab?

Our project seeks to develop a system capable of limiting the amount of active protein inside the cell, so that it is just the right amount needed. Therefore, we will use MeCP2's ability to bind to RNA and moderate its amount, in a natural way. This would be a good tool for Rett patients, but we should not forget that the MeCP2 gene is also involved in other diseases, such as some types of cancer.

I know that setting deadlines is always quite complicated, but do you think we are on the verge of seeing the first treatments capable of limiting the effects of Rett syndrome?

It is difficult, and it depends a lot on how the first gene therapy clinical trial that is starting right now in Canada goes, but I am sure that in a few years we will see great advances. If this first trial shows no toxicity and the therapy reaches the targeted brain cells, it will already be very good news. From here on, the system will have to be improved, and this is what we are working on in many laboratories around the world.

And it must be said that in addition to gene therapy, there are other parallel approaches, such as that based on IGF1, which is already reaching patients and improving some of the symptoms, since it helps in the maturation of neurons.

A final message for those affected and their families?

The families are the first to know that we have to be very cautious in the expectations we place on gene therapy, but in general the outlook is good because of the increasing efforts being made in research to obtain new treatments. They are giving their best and we cannot ask for more. I would say that we all need to put pressure on the institutions to do much more for rare disease patients, especially in covering their daily needs and improving their quality of life, in parallel to continuing to search for a definitive cure.