Profiles in Clinical Courage – Fragile X

This is the first in our series of blog post that focus on research being performed related to various rare diseases. Why focus on rare diseases? For the simple reason that these are the people who are not looking for glory, not hunting the big pharma exit, and in many cases are working with little funding and reward.

This is our way of giving them a shout-out and the recognition they deserve.  As an added bonus, we also get to learn about wonderful, new, rarely discussed areas of research.  You can’t ask for more than that! So let’s jump right in. 

Fragile X is a disease in the Autism spectrum.  We chose it because it is has a personal connection for many of us here at ClinicalBid. We reached out to a subject matter expert, Katie Clapp, who is the Executive Director and Co-founder of the FRAXA Research Foundation located in Newburyport, MA, USA.

ClinicalBid:Good morning Katie. Where are you hanging your hat this morning?
Katie:(laughs) In my kitchen here in Newburyport, MA.
ClinicalBid:First things first, thank you for joining us today. Please help us understand when/how Fragile X was discovered.
Katie:It's actually a great question to start with because it was known that there was something called Martin Bell Syndrome out there for decades. In 1943, Julia Bell and James Martin discovered a form of sex-linked developmental delay that is inherited from the X-chromosome. The syndrome was initially named Martin-Bell syndrome after its discoverers, but the name was changed to Fragile X syndrome.
In 1991 three scientists, all of whom we work with and have funded, discovered the gene that causes Fragile X Syndrome. In the words of James Watson who discovered the DNA double helix, this was the first big discovery, the first big public payoff of the human genome project.
So when Drs. David Nelson, Stephen Warren, and Ben Oostra discovered the gene, they also discovered the mutation that causes Fragile X, and they named it FRAXA, which is how we got our name. There you go! These three researchers were working in this tiny field and they made a breakthrough. Interestingly that was exactly the same time that our son Andy was diagnosed with Fragile X.
Dr Osstra, Dr Waren and Dr Nelson discover the Fragile X gene (1991)
ClinicalBid:I kind of figured there might have been a direct link to this for you. Is this mutation and population growing? Not growing?
Katie: The patient population is very stable. It is something that has existed for as far back as we can imagine. There's never been a first FRAXA mutation found that wasn’t inherited from a parent. On average, one in 5,000 people born have the full mutation for Fragile X and nearly 100,000 Americans, have the full mutation for Fragile X.
ClinicalBid:And I understand it's more prevalent in males than females.
Katie:It is. If you drill down, it’s more like one in 4,000 males and one in 6,000 females and that's not an accident. It's that girls have two X chromosomes and one is randomly shut down in in every cell of their bodies, brain and body. So with a girl you don't always notice because she may have gotten really lucky: if she does have a full mutation, the X chromosome that shut down in each of her cells might be the one that had the Fragile X mutation. A girl could be entirely unaffected if all her cells flipped the coin the right way.
ClinicalBid:Got it. Obviously it's a personal mission of yours, but what is the overall organizational mission?
Katie:FRAXA Research Foundation’s mission is to accelerate research to find effective treatments and ultimately a cure for this disease. We directly fund millions in Fragile X research around the world.
ClinicalBid:Given all of the advancements in genetic editing, do you feel like ultimately there might be a way to develop a cure?
Katie:Oh yes. There are a number of approaches that we're funding right now that, we think, would essentially lead to a cure. In cells in the lab and in live mice, it is possible to edit the gene or to deliver a new copy of the gene and have it function. Another approach we are testing is delivering FMRP – the protein product of the Fragile X gene which is lacking in the syndrome.
ClinicalBid:Are you seeing a reversal of some symptoms?
Katie:Yes. FRAXA is funding a team at the University of Calgary, and they have injected a shortened version of the Fragile X protein into the tail vein of Fragile X knockout mice. Believe it or not, that got in the bloodstream and to the mouse brain, which is amazing
ClinicalBid:You mean it made it from the tail through the blood brain barrier? How did the mouse present prior to and after treatment?
Katie:Before treatment, Fragile X mice are hyperactive. But treatment reduced hyperactivity characteristic of Fragile X syndrome for at least 24 hours in live mice. On a cellular and network level, it corrected a number of very complicated abnormalities. For all the fun details check out
So now there are genetic approaches to a whole slew of mouse models that have been developed where they can actually switch the Fragile X gene on or off in the whole animal. And when they do that, yes, they can reverse all the symptoms they look at -- except for one. So proof of principle is that yes, if you're able to express the gene the way it's supposed to be expressed, you can reverse Fragile X.
ClinicalBid:Do you want to share with us what the one nonreversible trait?
Katie:Kind of funny. They basically took Fragile X away. When they switched on the silenced gene in adult male mice, all his hyperactivity and behaviors and learning problems reversed, but his large testicles did not shrink.
ClinicalBid:(laughs) Okay. Poor mouse. Switching it up a bit, help me understand what are the manifestations of Fragile X?
Katie:The key aspect to understand about Fragile X is that it is the most common inherited form of autism. And that matters for all your readers and for all of us because studying Fragile X is really one of our very best ways to make progress on autism. And certainly, any treatment that's found for Fragile X has great promise for autism.
Autism is not a rare disease. It's huge market. There is so much unmet need, but they've got almost no animal models to speak of because they don't clearly understand the cause.
ClinicalBid:As you know there's a very large argument on the Internet about whether autism is inherited or a result of epigenetic modification.
Katie:Right. And nobody knows the answer.
ClinicalBid:How many different schisms are there within the autism or acknowledged within the autism spectrum?
Katie:Well, Fragile X is the largest single cause -- I mean the largest single inherited cause. There are many other genes that are related to autism. Fragile X is the largest subset. It's also the best developed in terms of research in animal models and treatments. It is really important for researchers trying to tackle autism.
ClinicalBid:Are you the number one organization with respect to funding around Fragile X research?
Andy (age 30) with alpaca
Katie:Yes, we are.
ClinicalBid:So you're leading the charge here correct?
Katie:We're fortunate that when we started, Fragile X was understood, although just barely. Not only did those three scientists discover the FRAXA gene mutation, but the next thing they did was to understand that the mutation shuts the gene down so it cannot produce its normal protein product. The very next year they cloned the protein. They could make buckets of this stuff. And then we knew that what was wrong with our kids was they were missing a protein. So about three days after Andy was diagnosed, my husband, who is a physician, came back from a medical school library and said, “You know, this is potentially treatable. Andy is missing a protein. Just the way diabetics can't make insulin.” It’s not as simple as feeding them the protein and but it opens all the doors.
ClinicalBid:This is a natural segue. You said, hey, they're missing a protein and if we could somehow get the protein into their system it would help.
Katie:To summarize, in 25 years, first we figured out what was wrong, so we know they're missing a protein and we know that protein has key roles at brain cell synapses. Can we replace the protein? Can we reactivate the gene? Or can we find drugs that can take the place of the missing functions? We have been going down all those paths. Sometimes things are not as easy as they look. You can't just dump the missing protein into the brain. It's tightly regulated. It’s like a spark to gasoline. It must be done in a regulated manner.
ClinicalBid:Perhaps even individualized as we have all have different brain chemistries, right?
ClinicalBid:That's fascinating though.
Katie: Absolutely! We all know that to get that right is going to take many years. There's a potential cure. In the meantime, if we can find the right small molecules in the right combinations, maybe we could compensate for what's wrong. The question is how do you find that out? We have contracted with a company based out of Cambridge, England, which uses Artificial Intelligence (AI) to tackle that. Healx has been given prizes by the Queen and we're kind of their first big test case. Over the several years we have worked with them on this project to generate a Top Eight list of available drugs which not just treat symptoms but reverse it at the neuronal level. We are now looking at combinations.
ClinicalBid:So you're telling me that you’ve come up with a treatment that affects the chemistry in the brain?
Katie:It normalizes brain function on the network level.
ClinicalBid:Why aren't you all over every headline in the world?
Katie:Clinical trials are needed to prove it. We are only at the level of having sent these compounds down to FRAXA-DVI, our Fragile X mouse testing facility to carefully check them out.
ClinicalBid:They developed AI models. You've been able to basically go through a number of compounds, identify more promising models, and then you've applied them to mice
Katie:There are 1400 or so existing, approved drugs and those can be run through panels with AI as a high throughput screen. A lot of groups do drug screens, but the key is what do you screen against? This started with testing those drugs on several different cells from Fragile X mice and stem cells from humans with Fragile X and then picked out the compounds that best normalize those test cells. Then there's an AI piece of it where they run through all that's known about Fragile X. Then there's discussions with our scientists, particularly my husband, Michael Tranfaglia, MD, who is on the Healx scientific advisory board. Finally they could winnow the options down to the best ones to test on live mice. And now we need clinical trials for patients with Fragile X.
ClinicalBid: When you say trials, you're talking Phase Zero.
Katie:Actually, these are approved medicines which have already passed safety testing. These are drugs that could be given tomorrow. We just need to know which ones are most promising.
ClinicalBid:Are you saying because the drugs have already gone through the safety testing, you don't have to do that again?
Katie:Right. There are eight drugs that are showing promise but we need to get some solid data to proceed. One drug is probably not going to cure Fragile X. It's complicated.
ClinicalBid:Even the reversal of any symptoms to a certain level is going to be considered miraculous. You're kind of blowing my mind! Let’s talk about what's holding you back. What are the roadblocks?
Katie:Money, honey! Clinical trials are the most expensive phase of this entire effort to find treatments.
ClinicalBid:Given the promise that you hold, I think your fundraising would be pretty amazing. Although I do remember looking in the World Health Organization database, there weren't a lot of trials listed there. I think there were three or four that were recruiting.
Katie:Well, you know, it's just possible from business point of view that we've been too tight with our money, but we started this with the promise that everything we raised would go to research. So we're not spending a lot on the organization and you've got to do that to grow. So you know, you can imagine what it's like to try to manage every one of these and, and optimize them and run meetings and explain to every person who might give you $25, the promise of it, and then not know how long it's going to take.
ClinicalBid:If I were to compare you to other rare diseases or some diseases as a whole, you at least have some promise. You can say to people that we have the cause and we may be able to reverse some of the symptoms or cure this within your lifetime. Others cannot even say that it will happen.
Katie:It will happen. And while we are searching for the ultimate cure, which we know has a ways to go, combinations of medicines already out there hold some really amazing promise. And the reason I'm not talking more about that is that it's kind of like, where do we start? I mean to go in and recommend to your friends that they try this and this and this. How do you deal with the fact that you've got three-way combinations to consider, and you don't know what doses and how long each trial is going to take? So anyway, this is where we're at, but it is exciting.
ClinicalBid:My cousin's son is on the autistic spectrum. When we end our call, I'm going to go on Facebook and send her a message asking if he has been tested for Fragile X. Now I'm just dying to know! To wrap this up what would you want everybody to know?
Katie: That we're on the path. Our organization has kept true to the mission and we will always, because we are parents. It keeps us honest. Clinical trials are mind-blowingly expensive. We need to get the funding and do these trials. We will get this done.
ClinicalBid:Well, we will be sure to do our best to help get the word out. We will also include the various weblinks so that our readers can find you and hopefully help you. Thank you so much for your time and all of the information you shared.

Niagara Falls is one of 21 landmarks lit up in FRAXA signature teal to mark Fragile X Awareness Day

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