Authors: Alice Weatherston
Alan Percy (University of Alabama at Birmingham; AL, USA) has more than 30 years of experience in pediatric neurodevelopmental disorders and is an internationally renowned researcher on Rett syndrome. We talked to him on Rare Disease Day 2016 to find out more about his career and current efforts to identify a cure for Rett syndrome, as well as the importance of rare disease research more generally.
Can you introduce yourself and tell us a little about your career?
I am a pediatric neurologist. I did my training in child neurology at Johns Hopkins University (MD, USA) and I have subsequently had academic positions at UCLA (CA, USA) and at Baylor College of Medicine (Houston, TX, USA), before coming to the University of Alabama at Birmingham in 1992, as a director of child neurology. As I’m now past retirement age I have stepped away from that role and now run a clinical study looking at the natural history of girls and women with Rett syndrome, other individuals with mutations in the Rett syndrome gene but not meeting criteria for Rett syndrome, or in the case of males, those who have duplications of the gene.
I have always worked in basic science research, looking at neurodegenerative disorders in children. However, whilst I was in a laboratory at Baylor I was also a consultant to a child development clinic at the Texas Children’s Hospital. One day in 1983, just after the publication of the first widely read English language paper on Rett syndrome by Bengt Hagberg and colleagues, I was asked to see a girl who was said to meet the criteria for the disorder. I confirmed the diagnosis of Rett syndrome and following this, after showing her to my colleagues, we recognized another half dozen girls with Rett syndrome. This is where my work in this area began. Before I left Baylor we had accumulated over 150 girls who met the criteria for Rett syndrome.
At Baylor I also worked closely with a child neurology trainee, Huda Zoghbi, whose laboratory went on to identify the gene mutation associated with Rett syndrome, MECP2, in 1999. With the recognition of the MECP2 mutation I then set out to look for the impact of specific treatments on the disorder, but soon realised that we really needed to understand more about the natural history of the disorder. So, in 2003 we began to collect natural history data. We now have such data on more than 1000 girls and women with Rett syndrome.
What natural history data do you collect?
What we basically do is evaluate the girls and identify those that have mutations in the MECP2 gene using the set criteria that has been established internationally, as more than 96% of the girls have mutations in this gene. Different mutations can of course cause different degrees of severity, among other factors, so what we do is collect a large set of data on all aspects of their development, motor capabilities, behavioral capabilities and stereotypic abnormalities such as hand movements, unusual patterns of breathing, and small size or unusual patterns of deceleration of brain growth.
Once we have data across a large number of girls, many of whom have the same mutations, we compare and contrast to see if each girl with each mutation is similar or not. In fact they’re not, but if you look at different types of specific mutations in an aggregate you can see that some girls who have mutations in certain areas of the gene are much more severely impaired than those who have mutations in other areas.
Do you have any other studies currently being carried out?
In the last two or three years we’ve been gearing up for a couple more studies. Specifically, we have started to become involved in clinical trials with compounds that companies are suggesting may be of benefit for Rett syndrome patients. These compounds are not curative however; we regard them as disease-altering.
I can’t talk about the specifics but what we are doing is testing our compounds in both younger girls and in adolescents and women to see if these agents can improve the capabilities of these girls in a number of different regions. One of the agents that we are testing is principally focusing on breathing abnormalities and the second agent is more generic in its outcome, looking for more general improvements which could include breathing, interaction, hand use, mobility or something else.
These are at the stage of early Phase II in the first case and late Phase II in the second case. The principal outcomes are still safety and tolerability but we also have other secondary outcome measures where we’re looking for therapeutic benefit.
What are the current therapeutic options for Rett syndrome then?
As with any child with a neurodevelopmental disorder the general approach is based around the fact that they need to have a very good feeding regimen, because as I said, these girls tend to be small and in many cases don’t eat properly. In around 30% of cases the girls have to be fed through a gastrostomy tube directly into the stomach, some of these girls use them solely as their means of feeding and for others it’s used as a supplemental route. They also need physical, occupational and very special speech therapy, as most of these girls do not talk or use vocal communication well.
Are there therapeutics currently being tested that are designed for ‘cure’ rather than just symptom treatment?
From the beginning, because this is a genetic disorder, we always thought that there was potential for affecting major change, if not cure, of the disorder. There are a number of issues related to that however.
The first issue is early diagnosis because if you’re going to make an impact on a neurodevelopmental disorder you need to do it as soon as possible. The average age of diagnosis at the moment is around 2 and a half years of age. We’re working very hard to try and push that down but that is still potentially a bit late. It’s difficult however because the main clinical feature of the disorder, that is the tip off for diagnosis in most of the girls, is a regression in their developmental skills and that usually occurs between 12 and 30 months, so you’re already a little bit behind.
In terms of research into gene therapy, due to the fact that there is a genetic mechanism to the disorder, you could theoretically reinsert a normal version of the gene into an individual and affect either a cure or a near cure. There is some animal evidence from Adrian Bird’s team at the University of Edinburgh (UK) that suggests that mouse models engineered with the reinserted gene controlled by a specific receptor can improve a great deal once the receptor is activated and the gene turned on. But there are several questions that need to be considered.
As the Rett syndrome mutation is located on an X chromosome its effect is such that it tends to produce the disorder in females, where they have two copies of the X chromosome. In every cell in a female, one of those copies is generally silenced or inactivated. So, on average, half of the cells in a girl with Rett syndrome will be normal, in terms of their X chromosome, and the other half will be abnormal. This is not always true, this 50/50 can vary a great deal, but if this is the case and you supply a gene to a cell in a female, you don’t know whether you’re putting the gene into a cell which has the normal chromosome working or the abnormal chromosome. That is a theoretical concern but as mentioned before I don’t think that’s actually turned out to be a problem in the animal studies that have been done so far.
Another issue however is getting the gene into the brain – that is not a trivial pursuit. Currently, the mechanism being utilized is to attach the gene to an adeno-associated virus and attempt to get this into various cells in the brain. How to do that is still under study; it could be done via injection into a vessel outside of the brain, into the spinal fluid or directly into the brain.
The second route for genetic treatment is attempting to reactivate the normal X chromosome in those cells in which the abnormal chromosome is working. You need to do that in a way however that would not alter the already active normal chromosome in the other cells of the body. This is being worked on aggressively in a range of laboratories including at the University of Massachusetts (MA, USA) and at the University of North Carolina (NC, USA).
There are therefore two potential treatments involving the gene which I think have great theoretical potential, but in practice, and I would like to be wrong, I think it will be 10 or 20 or even more years before that is achieved. It is possible though.