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.
So at the moment do you think it’s more the development of therapies to treat the symptoms of the disease that will benefit patients?
Absolutely, we can’t just sit around and wait for a cure, we have to do as much as possible. Parents are pretty much demanding it and we are eager to improve as well. However, you can do a lot just by providing better diagnostic care, better recognition of the disorder and the routine therapies I mentioned previously; physical, occupational and communication. The girls that we have seen since 2000 and probably since 1995 are much healthier and have a much longer life expectancy than the girls we saw initially back in the 1960’s and the 1970’s. We have been able to reduce the frequency of problems such as contractures in the knees due to being confined to a chair, as well as scoliosis.
Of the patients Andreas Rett saw back in the1960’s and the 1970’s, no one was over the age of 25. However in our study Kaplan-Meier curves have indicated that the average survival of girls or women with Rett syndrome is now slightly over 50 years of age, so that’s quite different! This also has certain connotations though, as if the women are in their 50’s it means their parents are correspondingly older, making it a public health maintenance issue of how to deal with these individuals when their parents are perhaps unable to care for them any longer, or to the same degree.
We have also more recently become acutely aware of the social factors associated with this extension in life expectancy. At least in this country, children with disabilities can go to school until they’re 22, but once they reach this age they are out of the school support system. Very few communities have programs for these older girls or women to enter which will continue their socialisation so in many cases the girls then have to stay at home, which causes problems for both the girls and the carers.
Do you think setting up social programs then is important for these patients?
Absolutely, we can’t just look for the ‘golden egg’ of a genetic cure; we have to manage the problems that are at hand until such time as that cure, if it ever comes, arises. The approaches to this disorder or any other similar disorder are multifaceted.
We try to insist that the families begin to look for social programs before the girl is in their 20’s. In the Alabama area specifically we have something called the Southeastern Rett syndrome association that does work to connect families and to try to stimulate the development of social programs as best as it can. The parent advocacy groups are really the agents that are pushing these programs.
Do you think the role of parent advocacy groups is heightened in rare disorders such as Rett syndrome then in comparison to other pediatric diseases?
I think pediatrics in general is special, for most disorders that are significant, whether it’s asthma or Down syndrome or rare disorders such as Rett syndrome, the parents become quite energized and patient advocacy groups become very important. It’s perhaps a little bit more difficult to generate these advocacy groups for adult disorders but we know in the rare disease network, in which we are engaged, that there are many adult onset disorders that have very good patient advocacy groups. It simply takes the energy of some group of people to begin to focus attention on these disorders.
Does that kind of interest from patients help at all in getting funding for research?
Funding is certainly an issue. In Rett syndrome I think we’ve made so much progress over the past 10 or 15 years that perhaps the situation isn’t as bad for us as it is for others, but it’s still difficult to find out about research funding. There is a substantial amount of money available at the NIH level but you have to have very good preliminary data in order to get their attention. The patient advocacy groups in Rett syndrome have been very effective in raising money and supporting small pilot projects which help generate this preliminary evidence that will hopefully lead to broader funding at the national level. There are also local communities though. We have one group here in Alabama which are very aggressive in raising money which is going into a fund supporting the research here at the University of Alabama. You have the big dollars at the federal government level but you also have lesser amounts from the patient advocacy groups and even smaller seed funds at local institutions or from local communities.
What do you hope will be the next big development for Rett syndrome?
There is a substantial amount of translational work going on. In animals they’re testing a variety of compounds that are thought to have an impact on at least the animal models of Rett syndrome and if those can be used in humans or modified in a way to make them safe for use in humans then we look forward to advancing those to clinical trials. The downside, or foreside, of that is that the rare disease sector is still a relatively small group and trials are limited by the number of patients, as you can only trial a particular compound in one individual at a time.
I’m hopeful that more and more agents will become available. I know of other smaller trials that are going on in this country and I’m certain that there are others going on across the world.
I am on the safety monitoring board for the IGF-1 study, which will be continuing for at least another year and perhaps a year and a half or two, expanding to different institutions, but that is the only trial I know that is that far along. There were no safety issues in the first stage of the study so efficacy is now being investigated. One of the issues with the IGF compound however, is that it is limited to use in children because it is a growth hormone which could theoretically cause abnormal bone growth in adults that have stopped developing.
We ourselves are beginning a trial with a short compound related to IGF-1, it’s a Neuren compound termed NNZ-2566 or trofinetide, which was trialled first in older individuals. Now we’re carrying out the trial in younger individuals, again to test safety mainly, but if that’s effective it would be advanced to a pivotal trial. I suspect that that would be 3–5 years in the future.
What I’m saying really is that every trial takes a certain amount of time, which is frustrating for those doing the trial but it’s also frustrating, if not more so, for the parents who have to wait.
As it’s Rare Disease Day, how important more generally is research into rare disease and is it something that we should be paying more attention to?
Absolutely, rare diseases were pretty much ignored throughout most of the 20th century and there were a number of different groups that were responsible for bringing this to the fore. There are approximately 7000 rare disorders and in the US the definition of a rare disorder is that it affects 200,000 people or less, in Europe it’s a slightly different definition but it plays out similarly. If you take everybody who has involvement in one of those rare disorders in the US it totals approximately 7–10% of the population. That’s a substantial number and it has important public health issues so to just ignore it I think is no longer possible, especially as advances in medical care means these patients are living longer and longer. Rare diseases have become very important, I think they still need to be pushed, but there’s been a major boom in the last 15–20 years and I only anticipate that it will get bigger.
The opinions expressed in this interview are those of the interviewee and do not necessarily reflect those of Neurology Central or Future Science Group.