As a charity that is focused solely on raising funds to support research into treatment for Rett Syndrome and related MECP2 disorders, we talk a lot about finding a cure. But how will this happen? What do we mean by a ‘cure’? Why do we think there are such strong grounds for hope that an effective treatment is within sight?
To understand this, it’s important to understand what causes the condition. Rett Syndrome is caused by a single gene called MECP2 that mutates – changes permanently – at the point a child is conceived. It is this mutation that means the child will go on to have Rett Syndrome.
The MECP2 gene can mutate in a variety of different ways. Genetic testing – which is often used to confirm a Rett diagnosis – can pinpoint the exact type of mutation a child has. And parents often ask at this point what the prognosis is. As parents, we’ve all asked it: “What does this particular mutation mean for my daughter? How severely affected is she? What will she be able to do?”
But it isn’t quite that straightforward. There is no simple correlation between mutation-type and severity of Rett-symptoms.
Instead, there are two main explanations for differences in severity between different individuals – and understanding these will help us move towards effective treatments.
The first explanation is different patterns of X chromosome inactivation.
This refers to the number of cells in a girl’s body in which the mutated gene is active. The mutated MECP2 gene is on the X chromosome. Females have two X chromosomes – and in every cell of their body, one X chromosome is ‘active’, and the other is ‘silent’.
This active/silent pattern is usually random, which means that around 50 per cent of cells have one active X chromosome and 50 per cent have the other. But sometimes this pattern is not random, but appears skewed – where one chromosome is ‘favoured’ over the other.
If a girl with Rett Syndrome has a skewed pattern where the X chromosome with the mutated MECP2 gene is active in more cells than not, her symptoms will be more severe. (And vice versa – if the X chromosome with the healthy MECP2 gene is more active, she will be less severely affected.) We know from looking at identical twins with Rett Syndrome, who have the exact same mutation but different symptoms, that different patterns of X chromosome inactivation can make a significant difference.
If researchers could find a way of switching on the X chromosome with the healthy MECP2 gene – in every cell of the body – Rett Syndrome could potentially be cured.
The second explanation for differences in severity is the existence of modifier genes.
Looking at all kinds of diseases, we can see that the same disease affects different individuals in different ways. One reason for this is ‘modifier genes’ – something in a person’s unique genetic makeup that protects them against some aspects of the disease. Evidence suggests that some girls with Rett Syndrome have other genes that counteract the effects of MECP2 mutation.
If researchers could identify which genes protect against Rett Syndrome, treatment could be developed based on introducing these modifier genes.
The funds Reverse Rett raises in the UK are allocated to a range of research projects that aim to find treatment based on what we know about what causes Rett Syndrome and what affects the severity of the condition for individual girls.
There are three main approaches.
1. MECP2 as the target
We are particularly keen on this approach, because it attacks Rett Syndrome at its very root by seeking to switch off the mutated gene and switch on the healthy one. Research taking place at the University of North Carolina at Chapel Hill by Dr Ben Philpot and colleagues aims to activate the silent X chromosome that contains the healthy MECP2 gene. A big advantage of this approach is that there would be no need to deliver the healthy gene through gene therapy – because every girl with Rett Syndrome already has a healthy copy of the MECP2 gene.
2. Suppressor (modifier) genes
This is an example of the type of high-impact, high-risk project that we are keen to fund – because the potential rewards are so great. The aim is to identify which genes have the effect of suppressing, or modifying, the effects of the mutated MECP2 gene, as described above. It’s a bit like searching for the proverbial needle in a haystack. But Dr Monica Justice and colleagues at Baylor College of Medicine are beginning to see results. They are 15 per cent of the way through a project to ‘screen’ genes, and have so far found five potential ‘modifier’ genes.
One of the benefits of this approach is that it is helping researchers gain a better understanding of MeCP2, the protein produced by a normal, unmutated MECP2 gene. The exact function of this protein isn’t yet well understood, but one of the things it does is regulate other genes involved in brain function. It helps nerve cells (neurons) to function and to connect with each other. Girls with Rett Syndrome lack this protein, and as a result the neurons in their brain don’t connect as they should. (They don’t have brain damage: it’s the synapses – the points of communication between brain cells – that aren’t working normally.)
3. Downstream targets
We don’t always need to start from scratch with every treatment. There are drugs and treatments that are currently used to treat other conditions, but that may also have the potential to improve some of the most challenging symptoms of Rett Syndrome, such as breathing problems, seizures and disordered movements. Trials are already taking place in a number of locations, and we await the results.
Rett Syndrome Research Trust hosted an event in New York City in April 2013 entitled ‘Curing Rett Syndrome – how do we get there?’ Click here to watch a detailed presentation by Monica Coenraads explaining more about the current research projects we fund. You can also hear Ben Philpot discussing his work to find a way of reactivating the silenced healthy MECP2 gene as a treatment for Rett Syndrome.