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Dr Mark Hirst: Fragile X Research Update

Part 1: The Story so far

Dr Mark Hirst is a great friend to the society and had spoken at many family conferences. He is a molecular biologist, specialising in neurobiology based at the Open University. I hope our précis does justice to his excellent presentation.

Mark had an interesting “take” on current research and the thinking behind it. He produced a picture of an active volcano, saying how there was a lot of “blue sky” thinking initially in research. However, through all the build up along the way towards potential results, it could all literally explode in the drugs’ companies faces at the end if trials were not successful – that’s the active volcano bit.


  1. At the base of the volcano

  • The basic research involves looking at the bioactive molecules in the cells. The aim is to look for drugs or medication that will compensate for the lack of FMRP.

  1. In the clouds – the centre of the volcano

  • The pre-clinical trial stage is when scientists look at whether drugs have any effect on the fruit fly or the knock out mouse, both of which have been genetically engineered to have no FMRP. Looking at the neurons removed from skin cells has also proved significant in Fragile X Syndrome.

  1. The top of the volcano

  • OK so the drugs have improved things for the mice and the fruit flies. Now we move onto the actual clinical trials when scientists look at whether medications do anything to alleviate the symptoms of fragile X in humans. It is a big leap from flies and mice to humans. Many medications will have had safety trials already, in which case clinical trials can go straight ahead. Safety trials will be done on any medications that have not yet gone through that testing phase.

1. At the base of the volcano

Since 1980 there has been a steadily increasing trajectory of medical papers on Fragile X Syndrome, which has increased even more recently with a lot of positive things coming out. Mark felt this could only have a positive impact. A lot of research has focussed on the neurons in the brain. Neurons are incredibly small organisms surrounded by a lot of other cells. Part of how the brain works is through neurons communicating with other neurons and the points at which information is exchanged between neurons are called synapses.

In those with fragile X FMRP (the fragile X protein or Fragile X Mental Retardation Protein to be more precise) is absent from the neurons.

Everything that we do involves neurons being able to communicate or having that communication stopped. When neurons communicate with each other the cells move closer together, when they don’t communicate they move further apart. This is what helps to develop our brains –this is what happens when our memories are laid down or we learn new things.

Let’s look at this at the cell level.

FMRP acts like a brake on MGluR. When FMRP is not there, there is too much MGluR activity and this results in connections between neurons throughout the brain being altered with the cells literally “firing on all cylinders”.

2. Pre-clinical trials - the bit in the clouds

Understanding how the cells work has led to many drug trails in fragile X focussing on putting another brake on the MGluR activity to compensate for the lack of FMRP. Phase 2 or the pre-clinical trials have looked at drugs’ effect on the knock out mouse. However, many drugs have had an impact on this mouse, but not on humans with the result that the knock out mouse has turned out not to be such a good model as was originally thought. Partly this is due to the knock out mouse being genetically monitored so that every neuron is affected. Fragile X in humans is much more complex and very few individuals have a very simple absence of FMRP in every neuron. The CGG repeat length can also change in one individual so that some cells are making a bit of protein and some are even making the normal level of protein and are completely functional. There is no way of knowing exactly what goes on in any human brain. Blood cells (what is actually used to measure any individual’s CGG repeat length) actually give a poor approximation of what is happening in the brain. Hair follicles are actually a better model.

3. Clinical Trials – the top of the volcano

Individuals, who have made the best response to clinical trials tend to be those with no FMRP i.e. individuals most like the knock out mouse model. There are also issues around how to measure the effects of any drug on an individual and here there are differences of opinion. Many trials have looked at if the drug resulted in less behavioural challenges. The individuals who participate in any study will be looked at as a whole and what can often happen is that less behavioural challenges will have been observed in some, but not all of them. In this case it is often concluded that the trial has been encouraging, but the drug has been found not to work in all cases – things have been learnt but more work is needed. We know this from our updates in recent newsletters. The Novartis trial and Dr Sebastien Jacquemont research that compounds like ARFQ056 can have some beneficial effects, but not for everyone. But what then happens to the sub group of individuals who have improved under the medication? In many cases they are allowed to keep taking the drug.

Part 2: What can we expect in the next 2-5 years?

But all is not lost. Dr Hirst made these points

  • Some drugs will work for some individuals.

  • There will be more refined and targeted trials with existing drugs.

  • Researchers will be looking more closely at what they are actually measuring – is it realistic? Better measures will be put in place to determine any effects, which mean greater relevance in terms of fragile X itself.

  • Compound drugs are coming through from the pre-clinical stage, but, as yet, there is no information on their long term effects.

  • Researchers will be looking at, if they put the brake on the MGluR activity, does it go backwards?

  • All the new information gleaned will feed back into new trials

More targeted trials relating to putting the brake on MGluR Activity

Pre-Clinical Trials – what is in the pipeline?

Pre-clinical trials will continue to use the knock out mouse and the fruit fly, both designed to have no FMRP. The fruit fly is a good cheap starting point for drug trials. Actually neutrons are similar in many organisms. Hence how neurons talk to each other is similar in fruit flies and humans. Mice are quite like humans in terms of how the brain develops and afford researchers the opportunity to examine brain structures and test drugs easily.

What is exciting is that there are more targets for research being discovered. The role of FMRP has been further explored. 13 other proteins have proven to be present in Fragile X Syndrome. 7 of these have shown to be targetable by drugs or genetic assays (investigations) to reduce the impact of fragile X and put the brakes back on the MGluR activity. This could identify new targets for research and many people are doing basic research in this area.

  • Can researchers look at behaviours in mice that have a link with human behaviours in terms of the difficulties associated with Fragile X Syndrome? They have looked into how to assess the sociability of a mouse. This is especially useful in terms of fragile X as there can be arguments that what we are seeing in the knock out mouse is not really a good reflection of the behaviour being measured. Mice will use sniffing when they are anxious and so researchers can monitor levels of sniffing when the knock out mice meets a new mouse and when they come across a mouse already known to them and also when they are put in a new environment. They can look at whether medications continue to have a positive effect on the sociability of the mouse. This alongside the neurobiology that underpins it can have a positive effect on companies going forward to do trials.

However, big questions remain; how long do the effects last and what happens within the brain itself when cells communicate with each other?

At a pre-clinical stage models are proving useful in terms of directing research. They show there are

  • More drugs to test including combinations of drugs

  • Stability of drug effects

  • Genetic therapies

There are also big projects looking at the genes/processes involved in Autism Spectrum Disorders and other developmental delays that will impact on research into Fragile X Syndrome.

And there’s more:

There are also things further back in the pipeline – at the stage before pre-clinical trials i.e. at the base of the volcano, looking at what happens at cell level. The role of FMRP has been studied and it has been found that it regulate other proteins as well.

Identifying the involvement of these other proteins regulated by FMRP has highlighted potential targets for research. Research into Autism Spectrum Disorders is focusing on the conversation between cells and 120 FMRP target genes have been found to be associated with Autism Spectrum Disorders. This will give researchers into fragile X the opportunity to hitch onto bigger science projects.

At this cellular level sophisticated microbiology is taking place. A new function for FMRP that does not involve regulation has been identified. It is concerned with the transmission of the signal along the axon, which is part of the nerve cell taking information away from the cell body. The electrical signal that takes place at the point of communication between cells can now be measured. Antibodies that take away FMRP are being investigated.

These are all new domains for FMRP research and are leading to new targets for potential investigation and research. A lot of work still needs to be done to identify critical targets, but it is likely that trials will involve existing drugs (i.e. safety trials have already been done) so researchers can go straight to the clinical trials stage. Companies have back catalogues of drugs cleared for safety and there are funding mechanisms in Europe.

Researchers have ended up with more FMRP targets than they can cope with. The key now is to identify the important ones.

And Finally

  • At the moment those individuals affected by Fragile X Syndrome, who have responded best to drug trials, are those producing no FMRP – those most akin to the knock out mouse model. Researchers want to look at why some cells produce some FMRP and others don’t and then transfer this to the knock out mouse model.

  • Dr Hirst felt that a recent publication was very exciting. A group has been looking into why the FMR1 gene (and thus the production of FMRP) gets switched off when the CGG repeat number hits 200. The publication highlights that, in those with a CGG count of over 200, the CGG RNA gets stuck to the CGG DNA and it is this that switches off the gene. This is a very exciting discovery and should lead to the identification of more drugs that might be targetable.

  • There is an already established brain bank for those who have suffered ataxia. Subsequently 3 brains in this bank have been found to be affected by FXTAS, which will possibly lead to more options for research.

  • Dr Hirst did touch on gene therapy as a possible way forward. It is possible to make FMRP, but what remains incredibly difficult is to get that FMRP into the right place in the neurons.

  • Minocycline is a medication that does not actually work on putting the brake back on the MGluR activity. Minocycline targets the protein synthesis as an antibiotic. It has been used specifically to enhance Speech and Language in those with Fragile X Syndrome.

  • Finally not enough is yet known about which areas of the brain are most affected by the loss of FMRP. This makes it difficult to be very exact about what drugs are likely to be of benefit. Different drugs may also work differently for different age ranges. As yet no drug has been trialled on younger children (under the age of 12).

So exciting times ahead!!!!!! Just to remind everyone you can look up clinical trials involving fragile X at

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