Over the past 20 years, I’ve gotten to know many people from all all over the world who are interlinked by one common denominator – CMT or Charcot-Marie-Tooth Disease. Despite cultural, social and economic differences, they share a common story, one which includes nerve degeneration, weakened leg/arm muscles, drop foot, claw toes, hand contractures, tremor, leg braces, foot surgeries, chronic pain and disability, just to name a few.
Some experience life-altering fatigue, easily broken bones, lack of proprioception due to loss of feeling, while others no longer have control of their hands or fingers and gasp for breath due to diaphramatic weakness. Some have even died due to complications from CMT.
Last week, I was speaking to a longtime friend, whose now 55-year-old son is bed-bound, unable to move, practically paralyzed from head to toe. His CMT, type unknown, has progressed rapidly, leaving this fiercely independent man completely reliant on the help of others.
His mom has been an extremely generous CMTA supporter for the past 30 years, and a supporter of the Cycle (and Walk!) 4 CMT event. When I heard just how much her son’s CMT had advanced, I felt angry. “I’m so done with CMT and its ravaging effects on my friends…SO OVER IT! I hate this stupid disease. It’s not only maddening, it’s depressing.”
I felt as though I had failed this family……and my own.
If only I could have done more to help her son….and so many others. I told her as much: “I wish I could have done more for him, for your family. It’s heartbreaking to think of him today, lying in that bed, unable to move. It’s disheartening to think of all my friends whose nerves are slowly degenerating as we speak. ”
Action empowers. Inaction disempowers.
If there is one action I can take, it’s to continue to support CMT treatment-driven research by fundraising, donating and ask others to do the same.
This chart shows the depth and breadth of CMTA research projects. 11 years ago, this was a blank page. Now we have 50 projects and over 30 partners, all funded 100% by individuals who believe in the power of our scientific endeavors.
Charity Navigator, America’s largest & most-utilized charity evaluator, also awarded the CMTA its highest rating last year (4-star), which fewer than 1% of charities receive. Now, that gives every one of us bragging rights!
My friend reminded me, “The CMTA is doing miraculous life-changing work and if it does not help my son, I know it will help others. Together, with our CMT supporters, we will make an indelible mark in this world. We already have!”
She’s right. With her words spurring me on, and with renewed energy, I decided to transform my anger into passion and drive.
So, yes, I’m asking again this year for your help because I want my son to have the best life possible. I want my friends to remain healthy and able-bodied. I want our future generations to be free of CMT.
So, instead of cancelling the Cycle (and Walk!) 4 CMT, we’ve decided to host a VIRTUAL event. Anybody, anywhere can participate. www.cycle4cmt.com
If you don’t want to get your walking shoes on or your bike out, you can sponsor a participant or a team…….like Team Yohan! Will you sponsor Team Yohan and help us advance CMTA research? If so, click here: https://cmta.akaraisin.com/ui/cycle/team/300635
And for the first time ever, Yohan is actually biking, thanks to a lot of practice, commitment to our cause and his e-bike! The plan? They are doing a classic ride across the Golden Gate Bridge and around the Marin Headlands on Saturday, August 29. Meanwhile, I’ll be in Crissy fields wearing a Shark Costume (Shark-O-Marie-Tooth) spreading CMT awareness and scaring little kids (kidding).
We also have a $50k match running in August, so your contributions will be doubled!!
That’s a lot of good news in one post!! Join us. Go virtual. Donate and leave a legacy of CURING CMT!
This is a transcript of the CMTA’s recent STAR gene therapy webinar. CMTA Board Chairman Gilles Bouchard begins by giving an overview of CMTA’s research initiative – STAR (Strategy to Accelerate Research), followed by an in-depth review of our gene therapy program by Drs. John Svaren and Kleopas Kleopa, members of our Scientific Advisory Board. These world-renowned researchers will explain what gene therapy is, how it can be used to advance treatments for CMT, and cover the latest advances from the STAR program. This webinar will also explain how we are preparing for clinical trials for many types of CMT.
STAR stands for “Strategy to Accelerate Research,” and it’s really core to the CMTA’s mission: our role is to accelerate treatments for CMT. In this work, we are driven by you and powered by you, the CMT community. You provide more than 80 percent of our resources, so, in essence, STAR is really your program. STAR is for you, and by you.
When we started STAR over 10 years ago, we really wanted to take a business approach. We wanted to bring the rigor, the focus, the accountability that you have in a business.
When you run a business, the first thing you do is try to figure out your strengths and your weaknesses, and the best strategy to be successful.
Taking drugs to market is a tough business, and it takes well over 10 years on average to develop a drug. Most new drugs fail in clinical trials. And it costs hundreds of millions of dollars. So how do we make this attractive to partners? How do we accelerate research?
One of the most attractive things about CMT is that for most types we have very well-defined genetic causes. CMT is what the scientists call a monogenic disease, which means we can replicate and test this disease in the laboratory.
There are also a lot of new therapies and technologies to address genetic issues. And those play right into what CMT is as a disease.
Biotech companies once looked at CMT as a slowly evolving disease, which would therefore require very long and very expensive clinical trials. If anything, this has been the biggest inhibitor for pharmaceutical companies to get involved in developing drugs for CMT. So more than 10 years ago, in partnership with the Inherited Neuropathies Consortium (INC), we embarked on a major effort to develop what are called biomarkers, and also to develop an important clinical infrastructure so it would become much easier, faster and cheaper to run clinical trials on CMT. We have made tremendous progress there. And this barrier is really starting to crumble.
Finally, from a business point of view you may think being a rare disease is a disadvantage, but because of the laws in the US and in Europe, it is actually attractive for companies to work on rare diseases. There are some advantages for businesses on the tax side and the protection of intellectual property.
So, if attracting partners is the core of our strategy, how do we make CMT attractive to partners? We need them because even though we’ve raised a lot of money from this community, we don’t have the billions of dollars it takes to develop drugs. In working with partners, we found that there are five key things they look for.
The first one is what they call KOLs (Key Opinion Leaders) or experts. In general, companies are experts in drug development, but they don’t know CMT very well. So they want to engage with CMT experts. That’s why we built our incredibly strong Scientific Advisory Board with over 30 great scientists.
The next thing they want is the ability to test in the lab, what we call preclinical tests. This is how drugs are developed, and we spent a lot of effort building a very broad, very powerful preclinical testing infrastructure. When they contact us and see what we’ve developed thanks to your support, they tell us that they feel like kids in a toy store!
The third one is clinical trial readiness. This was a major inhibitor for CMT research and for companies. But again, we’ve made tremendous progress, and we feel that we can run much shorter clinical trials.
That’s great on the medical side, but companies also want a strong, reliable and trustworthy business partner. What we found is not all companies are the same; they want different things. So we have to be flexible and adapt how we work with them on the business side based on what they need. Some companies, for example, are early stage companies that need money so we do co-funding with them. But others are loaded with money and they are looking more at licensing or buying technologies that we’ve developed with our partners. Other companies are looking at raising money, so we help them and engage with their potential investors. We have a lot of people with business experience on our board, and we really try to leverage this to help companies be successful on the business side as well.
Last but not least, what’s really interesting is that companies are very interested in engaging the CMT community, especially as they get closer to the clinical treatment of patients, because ultimately the CMT community is their market. So they want to know the impact the disease has on the patient community. Moreover, engaging patients is becoming very important as part of the approval process of drugs. In Europe right now you have to partner with a patient advocacy group to get a drug approved. And in the US the FDA is doing more and more of the same thing. So the fact that we can reach tens of thousands of CMT patients and that we have this really vibrant CMT community is a great asset for us and really attractive to our partners.
Now may ask, how is this working? We just put a few numbers together, and thanks to your support, we’ve made tremendous progress. We also realize that we have a lot of work left to do, but we feel like we’re in a really strong position right now.
We have a expert Scientific Advisory Board.
We have about 50 active projects, by the end of the year, we’ll have invested $15 million in CMT research.
We have developed really helpful testing tools for all major types of CMTs that our companies are using.
As a result, we now have 25 industry partners. That’s a really important metric—the one thing that makes us the most hopeful about the future. A few years ago we just had a handful of partners and it was hard to bring them in. Now people approach us all the time because they want to work on CMT with us. They want to use our tools and infrastructure. And you can look at these numbers, these 22 joint preclinical studies. Those are 22 actual studies that people are running this year using our infrastructure. Now, last year, this was only a handful. So in business terms I think we are seeing a bit of an inflection point: you invest and you work hard for a few years, and all of a sudden your business starts taking off. That’s what we’re seeing right now in CMT research. A lot of things are starting to accelerate!
And then we have this really wonderful, vibrant community—all the CMTA branches around the country and the CMTA Centers of Excellence. This has created a very powerful and helpful infrastructure, not just for us as a community, but also for our partners as well.
When we look at where to invest in STAR, we try to look at leverage points. So there are a lot of areas where we invest that cut across all CMT types or many CMT types.
We already talked about the testing infrastructure that we’ve developed that cuts across most types of CMT.
We will cover and go in depth today into gene therapy.
We’ll cover biomarkers as well.
Another area that’s quite interesting but we’re not going to cover as much is Axon Degeneration. It turns out that a lot of companies are working on ways to prevent nerves from degenerating for a broad set of neuropathies. And they want to use CMT as one of the rare disease indications for this. These companies are working with us now to try to find ways that to slow down or even stop the damage to nerves with some of their drugs.
Finally, you’ll hear about all the great progress on gene therapy. Obviously to apply gene therapy you need to know which genes to fix. So we’ve really doubled down on trying to find more CMT genes.
This is an overview of what we do across all types of CMT. Dr. Kleopa and Dr. Svaren are going to focus on a couple of them today, but keep in mind that while we won’t cover everything we do today, we have very thorough plans for each major CMT type and, in general, three or four key projects which are specific to each type.
Gene therapy is the use of genes or gene editing as a treatment. This process involves the introduction of genetic material, for example DNA or RNA, into cells and tissues of an individual instead of other treatments such as drugs or surgery.
There are different types of gene therapy, including replacing a faulty gene that would be a missing or mutated gene that can be replaced by a healthy copy of the same gene, or inactivating or silencing a mutated gene that has taken a toxic gain of function—a harmful effect on the body that occurs because the gene is functioning improperly.
And finally, editing a part of a mutated toxic gene that has a harmful effect—essentially a cut and paste approach where you selectively cut out part of the gene and replace it with a healthy part of the gene. This is a technically more challenging approach than replacing or silencing a gene.
How does gene therapy actually work?
In most cases we use viral vectors (tools commonly used to introduce genetic material into cells) to deliver the therapeutic gene. These viruses are used as vehicles to package and deliver our therapeutic genetic material. They have been modified so that they’re not infectious or contagious. They have the ability to enter the cell.
Once inside the cell they will release the genetic material and that will start the production of the protein, and this will correct the defect in the cell and be a treatment for the disease.
And here it’s important to note that this will be a once-in-a-lifetime treatment, so once the virus is inside the cell and releases the genetic material, it will stay and keep producing the protein that the cell needs to function.
Now let’s look at the types of CMT so that we can understand how we can apply gene therapy to CMT neuropathies.
First of all, nerves are bundles of many nerve fibers, and most of them are wrapped in myelin. They are similar to electrical cables, as you can see in the picture on the lower left, that are made of many wires and these wires have a plastic coating.
And in nerves this coating is called myelin. It’s an insulating and protective coating that is formed by specialized cells known as Schwann cells. Myelin is very important because it speeds up the conduction along the nerves by a hundred times, like going from 3G to 4G, but also supports and maintains the nerve fibers.
So depending on whether the damage is in the Schwann cells in the myelin or in the axons, we will have demyelinating types of CMT or axonal types of CMT.
In the diagram of a healthy nerve that would for example be a motor neuron, you notice that it starts with the cell body which is located in the spinal cord, and that sends a long extension all the way to our muscles in the arms or legs. This is the peripheral nerve. All along this nerve you need to have myelin and this is formed by Schwann cells.
There are over a hundred different genes that can cause CMT neuropathies. They have various functions in the cell, and this results in many different mechanisms. If the mutated genes are mostly expressed in Schwann cells, then you have a demyelinating type of CMT because myelin suffers first. But this will eventually also destroy the axon. And if the mutations are found in neurons then we will have an axonal type of CMT.
In addition, we classify CMT neuropathies by the type of mutation and whether this is a toxic gain of function mechanism or a loss of function. And that will also determine the gene therapy approach.
So what are the potential gene therapies we can use for CMT neuropathies?
We have to address the disease mechanism described in the previous slide. For CMT neuropathies that are caused by a loss of function of the gene (this is the case with most CMT4 neuropathies and CMT1X), we have to introduce a healthy copy of the gene, so that’s a gene replacement.
For CMT neuropathies with a toxic effect of the mutation (as is usually the case with CMT1 and CMT2 types), we have to either silence the toxic gene, repair it, or modify it so that we can prevent the toxic effect.
In addition, we have to deliver this treatment to the particular cell type that needs the treatment. So for the myelinating CMTs we have to target the Schwann cells and for the axonal CMTs we have to target the neurons, so that means a different approach because the cells are located in different parts of the body.
Now that you’re all experts on CMT genetics and gene therapy, let’s outline the efforts that the CMTA has spearheaded to try to bring new treatments to the clinic!
The science of gene therapy has actually been around for a couple decades. But there were a number of safety issues that had to be addressed. What has generated a lot of excitement in the last couple of years are treatments that are FDA approved for different diseases. The specific example we want to discuss is a disease known as Spinal Muscular Atrophy (SMA). This is actually a motor neuron disease, and it actually affects the same neurons that are affected in CMT. But SMA is a devastating disease that affects infants, and until recently there was really no treatment. But there are now two new genetic therapies that have been recently approved for Spinal Muscular Atrophy.
This includes AAV gene replacement therapy using viral vectors, just as we just outlined, by a company called Avexis. The diagram above summarizes how this therapy works, again by delivering the correct gene to the motor neurons. And there’s another genetic therapy involving antisense oligonucleotides (small pieces of DNA or RNA that can bind to specific molecules of RNA and block the ability of the RNA to make a protein or work in other ways) which we’ll cover a little bit later. The good news for SMA is that there were dramatic effects with both therapies, as long as they’re administered early enough in the disease.
We’re not only grateful for these advances for SMA, but they also provide us with an avenue we can pursue with CMT because it affects many of the same cell types affected by CMT.
To take advantage of this, we convened a gene therapy workshop for CMT in the summer of 2018 to get our plans together and take advantage of a number of different advances. We invited scientists and clinicians that were involved in SMA, Muscular Dystrophy, and different types of CMTs like CMT2D and CMT4J. There are also trials going on for Giant Axonal Neuropathy, or GAN.
We have number of assets that we outlined earlier. First of all, we had previously funded efforts of Dr. Kleopa to apply gene therapy and we’ll cover these specific examples in a minute. We have also partnered with other companies using ASOs. The animal models that we have developed are very important testing systems for development of gene therapy for CMT.
Another aspect that’s not to be neglected is the fact that we need to have good biomarkers (measurable indicators of the severity or presence of some disease state) and clinical trial planning expertise, which is critical for labs that want to invest in CMT.
And then ultimately we realized that we needed to recruit some leading gene therapy experts to our Scientific Advisory Board to lend their expertise and their advice as we move forward.
These experts include, Dr. Kleopa, from whom you just heard, who’s really pioneered a lot of the development of gene therapy for demyelinating CMTs. And then we have two additional experts: Steven Gray at University of Texas Southwestern, and Scott Harper at Nationwide Children’s Hospital. They are really leaders in the field, Dr. Gray for example is already engaged in efforts for CMT4J and another type of CMT (GAN). Recruiting these experts has been instrumental in us being able to plan how we can best use CMTA investments to accelerate the development of new gene therapy treatments.
With their advice we have formed a plan essentially to:
Develop a CMTA sponsored effort to target CMT2 using AAV9-based gene therapy. AAV9 has been used in other FDA approved treatments, and we decided initially to focus on the most common form of CMT2 which effects roughly 10 percent of people with CMT. This is caused by mutations in the Mitofusin-2 gene and is classified as CMT2A.
Our second objective is to develop gene therapy for CMT types 1 and 4, the demyelinating forms of CMT. Dr. Kleopa’s work in this area will be covered in the next several slides. Basically we need to optimize our approaches to improve delivery of the genes to Schwann cells. And we also definitely want to target the most common form of CMT which is CMT1A using another kind of technology called RNA interference.
And finally, we want to develop company partnerships that can help us actually bring these therapies to market.
On that last point, just one year after this workshop, we were pleased that our efforts met with some success particularly in our initiative to develop a new gene therapy for CMT2A. Based on studies by one of our board members, Dr. Robert Baloh, we found that there is a way to overcome the mutation in CMT2A.
We formed a partnership with one of the leading companies in the gene therapy space, Passage Bio. You may be aware of the announcement that came out a while back where we formed an alliance that will develop and test gene therapy using some of the rat models of CMT2A that were originally sponsored through the CMTA. This will be a broad collaboration, including the Inherited Neuropathy Consortium (INC), to sponsor preparations for clinical trials in CMT2A.
We should mention that we have other efforts on other types of CMT in discussion with not only Passage Bio, but with other companies as well.
We wanted to have a comprehensive approach for different types of CMT. The pie chart represents the different types of CMT ranging from the most common—CMT1A—to some that are much rarer. And the arrow around the pie chart shows the number of types of CMT that are covered under existing plans or projects, or ones that are under discussion.
We are well on our way to covering almost 75 percent of people affected by CMT with our ongoing projects, and we’re hoping that we can expand that in the future. This includes AAV delivery and many different technologies, and we’ll mention more about gene silencing and Antisense Oligonucleotides in a minute. We are trying to leverage success in one type of CMT to achieve success in other types as well.
Let’s look at two examples of gene replacement that we have developed for two representative types of demyelinating CMT neuropathies. The first one is the X-linked CMT which is one of the most common types. It’s about 10 percent of all patients, and this results from a loss of function of a gene that is important for Schwann cells.
Our strategy was to design a viral vector to deliver the healthy copy of the Connexin gene to Schwann cells. With several years of work we have shown that we can achieve a replacement of this gene in Schwann cells and, in the picture above, there are examples of an untreated and a treated nerve and you can see that the myelin structure has improved in the treated nerve. This translates also into improved function with better muscle power and improvement of the nerve conduction velocity.
This is an initial proof of principle that we can actually achieve a treatment for this type of CMT with gene replacement.
The second example is about CMT4C. It’s a rarer type of CMT but very important because it’s representative for all the recessive CMT4 demyelinating neuropathies. Like for CMT1X, we designed a vector to replace the mutated gene in Schwann cells. We showed that we can achieve the expression of the gene using this viral vector. The slide shows pictures of an untreated nerve on the left and a treated nerve on the right, and you can appreciate the improvement of the myelin structure and better preservation of the nerve fibers. This translates into improved motor performance. The muscle power is improved and the nerve conduction velocities are faster, again providing proof of principle for this technology.
Still we have a long way to go before we can reach the stage of clinical testing. We have now several lines of activities trying to optimize the tools in order to reach that stage.
Four major issues that we are trying to address include first of all the finding of the optimal viral vector. We’re focusing on vectors that have been already used in clinical trials, and selecting the best one to target Schwann cells. We also evaluate the best way of injecting these vectors that will be safe and easy to apply to patients. We want to make sure that these vectors have no toxicity—that they’re safe—and we also want to make sure they can get to the whole nerves around the body because this is what we need to correct in the demyelinating CMTs.
These issues are really crucial not only for the two types that we described before but for all demyelinating CMT neuropathies. So results from this work will be relevant for moving ahead with other types of demyelinating CMT.
We’re also focusing on optimizing the treatment for CMT1X using new and safer vectors, and we want to show that the treatment can benefit various CMT1X mutations both before and after the beginning of the neuropathy, which is a very relevant question for patients.
And for CMT4C we also developed a new vector that is safer to deliver the mutated gene and demonstrate that we can benefit the model. So we hope that this work will get us closer to clinical testing with the proof of principle that these treatments can work.
And we are very excited also to mention that this work has attracted interest from several biotechnology and pharmaceutical companies.
Although there are remaining challenges, we have confidence we can overcome them. The success achieved in CMT1X and 4C by Dr. Kleopa is actually encouraging for CMT1A, so we’re focusing our efforts to apply this technology to CMT1A, which is the most common form of CMT.
One of the reasons we have confidence in that success is due to another company collaboration with Ionis Pharmaceuticals, which uses antisense oligonucleotides (ASOs). CMT1A is a little bit different than the other types of CMT since there’s not actually a mutation of a single base but rather a duplication of the gene, so that you have excessive levels of PMP22.The work published with Ionis showed that if you use antisense oligonucleotides to suppress PMP22, you see in two different models of CMT1A a fairly dramatic improvement in the myelination. We are continuing to work with Ionis to try to perfect and refine and make more potent antisense oligonucleotides.
This success also made us realize that you can use a related technology known as RNA interference, or RNAi, to accomplish the same goal, that is, to reduce PMP22. In collaboration with Drs. Kleopa and Svaren and with Dr. Gray at UT Southwestern, we’ve just initiated a project that’s targeting the same technology used for CMT1X and 4C but that’s now targeting a model of CMT1A.
This is a three-part project where we continue to try to address the challenges that Dr. Kleopa mentioned, which is to optimize the delivery to Schwann cells, while developing and optimizing the RNA interference for PMP22, and then also trying to make this system as safe as possible by targeting this suppression to Schwann cells rather than other cell types.
Our efforts also include an exciting extension to the relatively new technology that many people have read about, which is sometimes referred to as genome editing, or CRISPR- Cas9. Many people have read articles about this and it has generated a lot of excitement in the field because this is actually a way to take mutations and actually fix them, so you really can fix the source of the disease.
This new technology is being applied and has entered clinical trials for some types of diseases, particularly for those in the blood stream where you can replace blood-generating cells relatively easily.
The extension of CRISPR-Cas9 to diseases affecting the nervous system will probably take some more time to do all the safety studies and refine the system. But we are really pleased to announce that we are partnering with one of the leading genome editing groups that has focused on axonal forms of CMT, 2A, 2E, and 2F. And we are also collaborating with a company called Toolgen which has developed an approach for CMT1A and has published some positive results.
While this technology may be a few years behind gene replacement therapy, there is a lot of excitement in this area and ultimately this will become a technology that will really spur development of novel therapies for CMT.
All these approaches depend on having good measures that can be used in clinical trials. When we talk to companies, they want to know how they can plan a clinical trial in a way that they’ll get a definitive answer relatively soon. And this has been a challenge for a slowly progressive disease like CMT. But we took this challenge seriously and we supported a number of initiatives.
Some of them have developed within the context of Inherited Neuropathy Consortium, which is partially supported by the CMTA. And there’s also been direct funding of CMTA of some of these efforts as well.
Looking at muscle MRI has turned out to be one of the most sensitive measures of progression in CMT. We are also looking at proteins in blood samples that can be used to measure neuropathy. We’ve used skin biopsies to develop other methods. There’s been a lot of work in CMT evaluation score development. And we’re also investing in wearable devices that can be used in the clinic or even at home to assess balance and movement.
The coordinated use of all of these biomarkers and outcome measures is such that we can hopefully provide companies and investors with relatively quick assessments of whether a clinical trial will be effective. And this is really crucial for those entities to be able to actually provide investment in these new technologies. Progress in this area is just as important as development of the gene therapy itself.
We covered a lot of ground in a few minutes here so let’s just take a minute to share with you how all the pieces of this puzzle fit together.
First, we learned there are two major types of gene defect: what we call “loss of function” where the gene stops working, or what is called a “toxic gain of function” where the gene starts doing something toxic to the body.
And there are three major technologies in gene therapy. Gene replacement, where you take a virus (AAV) and send a replacement gene; gene silencing, where you use technologies like RNA interference (RNAi) to interfere with the protein production; and gene editing, also known as CRISPR-Cas9.
What you see on this chart is how all the CMTA-funded projects and CMTA partners we discussed today map onto this matrix, and how the strategy we launched last year has already brought in great partners and projects across this spectrum, with more to come in the near future.
It’s also very important to be able to deliver the therapy to the right cell. For neurons (CMT type 2s), there is general optimism there because it’s been done before in SMA, for example.
But for Schwann cells (CMT types 1, X and 4), it’s a whole different challenge because you have to deliver therapy to the millions of Schwann cells which are along your nerves. So that’s why we launched this very important collaboration with Drs. Kleopa, Gray and Svaren to optimize delivery to the Schwann cells.
And finally, you have to deliver this to humans and run efficient clinical trials. This is why biomarkers are so important, and thanks to recent advances the scientists think that we can run clinical trials with fewer than a hundred patients in less than a year.
We’ve covered a lot of ground but this is not random, we are very strategic and thoughtful about where we invest and where we spend your investment.
We’re not done—there is a lot of work to left to do. And that’s why it’s important to continue support the STAR program. There are five key reasons that we ourselves support STAR.
The first one is that it is an incredibly strong program. It is recognized as the leading CMT research program. Top researchers and top companies are now calling us to work with us, and nothing could be more exciting.
We take very good care of our financials. We keep our overhead very low; 15 percent or less is our goal, and we’ve achieved that in the past two years. Most nonprofits tend to spend twice as much in overhead. Part of the reason for that, by the way, is thanks to you: because most of our resources come from the community, we don’t spend time chasing government money, big foundation grants, or running fancy fundraising events. That keeps us very efficient and very focused.
And we are recognized for this. If you look at all the independent evaluation agencies like Charity Navigator, we get very high ratings.
The other point, which is very unique to the CMTA, is that the board members—the people who actually make decisions—are also very invested themselves Over 20 percent of our resources and funding comes directly from board members, which means that the people in charge are voting with their own dollars. They put their money where their mouth is.
Finally, our strategy is based on partnerships, and our partners spend at least 10 times more money than we do. So, when you support STAR, your money gets multiplied by a big factor through the involvement of our partners.
We have all come into this for our own reasons and our involvement is very personal, but at the end we all have a role to play. Please get involved and be part of this incredible movement. At the end, this is your program, for you, and by you.
We have wonderful branch events and patient/family conferences around the country.
It’s really important to be part of the CMTA Center of Excellence network and to register with the INC. It will help our research and it will help you.
Because we have more partners, we have launched the Patients as Partners initiative, so you can be involved with companies.
There’s a lot going on, so please sign up for eNews and stay informed!
And remember the three Ws: you can help with work, with wealth and or with wisdom.
A big thank you to everybody. Remember: STAR is all because of you and everybody in the whole CMT community. We’re very proud of where we’re at today, but there’s a lot left to do and we need your involvement and support now more than ever before.
On the 10th Year Anniversary of the launch of STAR (Strategy to Accelerate Research), CMTA Chairman, Gilles Bouchard, gives a webinar explaining the current status and remarkable advances made in CMT research. This webinar was so informative and well-done, I transcribed it for you. Spread the word folks. Pretty amazing work being done right now.
Never before has the CMTA had so much treatment-driven research going on, and we continue to grow, expand and reach new people and partners. Please read up and I’ll give updates as the come down the pipeline. So thankful for our clinicians, scientists, volunteers for making this work possible. Thanks to all our generous supporters who make this vital work possible.
I’m the chairman of CMTA, and our family’s been involved with CMT and CMTA for almost 15 years. Our son Yohan was diagnosed with CMT about 15 years ago. So it’s been quite a journey for us, as for many of you, I’m sure. What I want to do today is give you an overview of the STAR program.
As you can see from the logo, we are celebrating the 10-year anniversary of STAR. STAR has been very successful, offering promise and hope for the 3 million people worldwide with CMT. Nevertheless, for people like you and for me, 10 years feels like an eternity when there are still no viable treatments for CMT. On the other hand, 10 years is actually a short period of time when it comes to developing drugs.
About 10 years ago, we had a CMTA board meeting to discuss our approach to research. We realized that while there was some good research and a few really brilliant researchers working on CMT, there wasn’t really a lot going on in terms of research that would bring drugs to market. And we asked ourselves, how do you accelerate research?
It’s extremely challenging to develop new drugs. On average, it takes 10.5 years from the time a drug is identified to get approval. The clinical part of this 10-year process takes about 8 years. Even scarier, 90% of the drugs fail during the approval process. And it costs hundreds of millions of dollars ……
So we asked ourselves, from a business point of view, how to accelerate this process?
From a research point of view, let’s look at the some of the positives about CMT:
The causes for the most common types of CMT are very well known, and more types are discovered every year, which is not the case in many diseases, especially for the nervous system. We can create animal models. We can create assays or cells in Petri dishes so we can create stem cells. Now we can test and create models of CMT, which are very valuable to our partners.
The other positive is that CMT is classified as a rare disease, which gives companies some advantages in the market. Although CMT is rare, it’s still fairly common and there are a large number of people with CMT, which is helpful for companies because obviously it’s still a big market and it allows us to have enough patients for clinical trials..
Since the CMTA has these models, we can take advantage of the latest developments in genetic and neurological therapies. As you know, since the genome was sequenced, there’s just been an explosion of technologies and applications, and many of those actually apply very well to CMT. So that’s very positive for us.
What makes it interesting for a pharmaceutical company to work on CMT?
Testing Infrastructure – We have developed a very extensive testing infrastructure. We created animal models, assays (tests). We created stem cells when they were needed. We also work with companies who specialize in testing animal models and analyzing tests. It’s what we call the STAR testing infrastructure, and it’s a very powerful infrastructure. In fact, most companies approach us because they’ve heard about this testing infrastructure, and they want to work with us on testing their compounds or their drugs or their ideas. And you’ll see, as I go through the details by each disease, I’ll give you examples of the things we’ve done there.
Key Opinion Leaders (KOL): Companies know their drugs and technology well, but they might not be experts in CMT, so they won’t have access to key opinion leaders, who are experts in CMT. This is why we built such a strong scientific advisory board – they collaborate with our partners and advise them on CMT. This creates strong teamwork and complementarity between their knowledge and the expertise of the companies.
Community Access. I always say that the CMT community is our biggest asset. Companies want to talk to the community to better understand the disease. They want to understand what’s called the burden of disease, how it affects people, how it affects people’s lives.
Almost every company tends to have dedicated resources to engage the community. Our CMT Association is a huge asset for us as we reach many people worldwide. And again, we thank you all for just being part of that.
Clinical Infrastructure: Once companies are done with the testing in animals or in assays, they want to test in humans and bring drugs to market. And this is where drug development becomes very expensive. Again, hundreds of millions of dollars are spent in clinical trials. And the more people you need, and the longer it takes, the more expensive it is, and that can often be an inhibitor for companies to work on the disease. It is especially challenging in CMT, because it’s a slowly evolving disease.
So how do you tell that a drug is working in a slowly evolving disease without spending years and years following a large number of people?
We work with the INC (Inherited Neuropathies Consortium), started by Dr. Mike Shy, who has involved many world-renowned clinicians and scientists. They had the vision to create this infrastructure like the Centers of Excellence (COE), where they see people with CMT. They do what’s called natural history, where we see how the disease evolves over time with patients, and then we develop biomarkers or ways to measure the progression of the disease.
The whole idea behind biomarkers is that we want to run clinical trials in just a few months with a handful of people, and get a good quality read whether the drug is working. And we’ve made tremendous progress here. And that’s a really attractive part for companies now.
Financial Support – We’ve learned that we have to be very flexible, and we have to provide the kind of support that fits their business models. So we work together on joint projects or even give them access to some funding through investors. We’ve learned to be very flexible on how we can help companies where needed.
STAR is based upon five core business principles:
Partnerships: We have announced five partnerships. The one thing we look at in terms of the measure of success is how many partners are we able to attract, how many phone calls we get a month about companies interested in working on CMT. And frankly, the last two years, it’s just exploded. So, besides the five that we’ve announced, there are actually eight more companies that we have not announced because they want to remain discrete right now. Again, they want to wait until their results are published to go public.
And we have a pipeline, meaning that we are in early discussion with another 15 more companies. Three or four years ago, there were only a handful of companies who were working on CMT. So this is probably the most exciting part as it shows that STAR’s starting to work because there is a long list of companies actually doing some work on CMT, and an even longer list of companies interested in trying to figure out how to work on CMT.
For reference, we also have five wonderful partners who help us work with pharma companies through all the testing procedures.
Sanofi Genzyme – is a very big company, and we started by screening their whole library, and basically, we’re down to one compound now, and we’re in the process of testing it, and we should know very soon whether it works successfully, and then we’ll decide what is the next step on this one.
But even more exciting is that we’ve actually grown that relationship, and we have now three other projects with Sanofi. There’s another family of compounds that they’re very interested in, and we’re actually testing those as well in CMT right now. They’ve also done some really good work with us on biomarkers, which hopefully will be published soon.
Lastly, we’ve done some work on what’s called target discovery where we have worked together on finding other potential drug discoveries or other compounds that targets CMT, and this has led to additional projects.
Ionis – You may have heard about the breakthrough with Ionis last year. They used components called ASOs, which go straight to the gene and really counteract the negative effect of having a duplicated PMP22 gene. That was a major breakthrough because they were able to stop and sometimes even improve the situation in two different animal models. This was probably the best example of showing that when you reduce PMP22, it actually helps the behavior of the animals – a breakthrough!
Now, they are basically working very hard in trying to design a drug for humans. Even though they have the drugs for animals, it’s obviously a lot more complex and challenging to develop the drugs for humans. They want a drug that’s very efficient, so that it can get to the nerves. We’re also in discussion with them about clinical planning.
InFlectis – We’ll talk in the context of 1B and 1A. Inflectis is a company in France that has developed a very interesting compound that has shown some exciting results in 1B and also in 1A.
Acceleron – You might have heard of Acceleron because we’re actually recruiting for clinical trials right now. They have a drug that helps rebuild muscles, so while it’s not a direct cure for CMT, it could really help people with muscle wasting caused by CMT.
Regenacy – one of several companies that’s working on what’s called axon degeneration. It’s a field that’s seen a lot of development the last couple years, where people try to find out ways to stop the degeneration of nerves.
To be the most effective with our resources, with our money, we find initiatives that cut across all diseases. Personally, I think it’s strategically something that is very important, and guess what? There are five of them.
Gene Therapy – You may have heard about CRISPR and gene editing. It’s a field that’s been around for quite a while, but it’s completely exploded over the last two or three years. There are close to 1,000 clinical trials in gene therapy around the world.
Currently, these efforts have only produced 2 new drugs; one of which which was approved in the U.S. less than a year ago for Spinal Muscular Atrophy (SMA). As we continue gene therapy research inside the lab, our ultimate goal is to transform it into effective treatments for people living with CMT. I encourage you to watch the PBS documentary: “The Gene Doctors” to understand my excitement, as it is clearly going to be a big part of our future.
Gene Replacement therapy also will be applicable to CMT. With gene therapy, scientists take genetic material, put it in a virus, and the virus goes in the nerves, and this genetic material kind of compensates for the gene that’s either missing or deficient. This suits CMT very well because we know the genes that are deficient, and we have models where we can test it. So people are very excited about applying gene therapy to CMT.
Now, a new branch of gene therapy that’s exploding and is relevant to CMT is CRISPR also known as gene editing. Here you don’t just put an additional gene material in the cell, but you actually go in there and change it – change the genome.
Axon degeneration – it turns out that there are a couple of really big markets that are driving this. One is chemotherapy, which creates a lot of neuropathies for people, and the other one is Diabetes. So a lot of companies are working on these diseases, and they are very interested in applying it to CMT.
And remember, from a business point of view, it’s always very interesting for a company to have a rare disease indication for a medication because they get the advantage of the rare disease while having the bigger market. So there are at least five companies we’re working with right now on different approaches to axon degeneration, and we’ve also launched several specific studies that we’ll talk about per the various diseases. And one of the beauties of axon degeneration is it could apply across CMT types, even the ones they are not diagnosed.
Models: It’s incredibly important to have quality animal models, usually mice, sometimes rats, and cell models or assays and stem cell. We can take people’s skin samples and make stem cells, and then we can make neurons or Schwann cells (Schwann cells make myelin) out of them.
Gene discovery: As you know, we’ve discovered a lot of CMT-causing genes. I think we’re up to 120, but there are still many types of CMT which have not been discovered, especially Type 2’s. It’s very important to continue that, especially in the context I mentioned earlier, that more and more of the new therapies are very gene-specific. So we need to continue to discover more genes.
Biomarkers – We are collaborating with the INC, which CMTA supports directly. Most of the funding for the INC comes through the NIH, but both the MDA and the CMTA provide additional funding, and then we have also funded several specific projects on top of it.
Biomarkers are important to track disease progression over time. Scientists are looking at elements in your blood. For example, Dr. Mary Reilly’s lab is looking at neurofilaments and her promising work is being published.
And then another project, again, in the blood, looking at what’s called microRNAs. This was funded by CMTA with Drs. John Svaren and Mike Shy and another company that we’re working with on this.
We are also looking at skin biopsies because you can actually detect levels of PMP22 in the skin. The CMTA is funding this encouraging project, spearheaded by Drs. Svaren and Shy.
We are also looking at MRIs of the calf muscle and looking at the fat content in the calf muscle, which correlates to disease progression. So, when you put all the three approaches together, we now think that we can run clinical trials over a shorter period, six months, with maybe as few people as 50, which is huge progress from the past when we needed hundreds and hundreds of people.
We’ve done a lot of work in CMT1A, and now we are funding efforts to address the other most common types, so you’ll see a lot of this for 1B, 1X, 2A, and other types. Now those biomarkers are again, elements that we look at in the blood or in the skin, but also, the FDA wants to see what’s called functional outcome measures. They really want to see the patients getting better. For example, with treatment, are people walking better, getting better use of your hands, etc….. So the team has been really busy coming up with the scores, which are functional in nature and which try to capture how much better people are or worse people are as their disease evolves, and try to do it in a way where we can see small changes, and also in a way that correlates with those biomarkers. The good news is there’s a major grant that was just approved by the NIH for the next two or three years to continue this work, so I think we’re going to be in very good shape.
We are also measuring activity in people’s homes with wearables. We’re looking at a proposal right now to look at some sort of wearable device where we could measure people’s gait, et cetera, when they’re home. This would give us an indication about diseases progression while at home which would give us a longer timeline and more information. .
Disease by Disease
CMT 1A – So, as you know, CMT1A is created by the duplication of the PMP22 gene, so the most obvious thing to do is to try to decrease the level of PMP22 in the body. We have the small molecule screen going on with Sanofi. We have the ASO approach with Ionis. We are now working with another company who actually wants to use CRISPR to decrease PMP22, so that’s very exciting, and actually, those tests are just about to start. And then also we’re looking at a very interesting proposal to kind of combine a gene therapy approach with an ASO approach where you would use a virus to send a little piece of RNA into the cells to try to interfere with the PMP22.
Now, besides the pure focus on PMP22, there’s been a lot of work done over the years to see this with other targets in the body that the new drugs could go after to help with CMT1A.
One in particular that’s shown some promising results is called P2X7, and we are working with two companies right now with drugs that target this. And they actually both are in testing right now.
We’ve done work to identify new targets, and we are actually funding a project that’s in full speed right now to look and see if there are other elements that we can identify that could help decrease PMP22. And then we’ve mentioned axon degeneration. This applies to all CMT types. If the work progresses well with other types of CMT, it could be very applicable to CMT1A.
We are doing the muscle regeneration work with Acceleron.
About two or three weeks ago, a company called Pharnext announced a Phase 3 clinical trial for CMT. The early results of their tests were encouraging. They showed that in some patients the disease improved, in others it was stable, and, sure, in others it got worse. But it was clearly better than the control group and the placebo. I think the general consensus around scientists is that this is interesting, and we want to see a lot more of the data as it becomes available throughout next year.
They will have to do this, obviously, as they engage the FDA, so it will be very interesting also to see how the FDA engagement happens. And we think all this will happen through 2019, so again, very interesting announcement.
So we all have to really help them in a way because they are defining how the FDA and the agencies think about CMT. Again, nobody’s been there before, so we’re working very closely with them, and all the patient advocacy groups are really involved.
It’s our first chance in a way to make the voice of the CMT patients heard to the FDA or to the European agencies, so it’s very important for us to all work together and basically make the voice of the patient heard. So this very first drug is going through this right now.
By the way, on the right is the CMT1X gene, and I think there are over 400 different mutations of the CMT1X gene.
There was a study on natural history that was just published. I encourage everybody to go to the Centers of Excellence and to go back because then our scientists can not only study your CMT, but see how it evolves over time, and that’s what’s called natural history. And this is one of the most important things that companies and pharmaceutical companies want to see, to really help them figure out how the disease evolves after the drugs get administered to people. So, there’s good data on 1X, and I think we’ll continue to see it happen in also in other diseases, but we need more and more patients to do that.
We just approved this year the funding to develop new mouse models of CMT1X. Pretty much all the work on 1X has been done with a mouse where the whole gene was removed, and it’s actually a very good model. But we feel it’s time to get more precise models with specific mutations, especially as new genetic technologies are coming into play. So we’ll need better models that we can just look at the specific gene mutations. So this is being funded, and it’s in progress.
We are also co-funding a Dr. Kleopa’s gene therapy project with the MDA . He has shown some really good results in mice, where he was able to get the gene material to the Schwann cells in the mice, and it did have an effect. So we continue to push on this project, and we try to find ways to make it more translational, meaning – how do we bring this to humans as quickly as possible.
The role of inflammation for CMT1X was highlighted by Dr. Martini in Germany. And there are several companies that we’ve talked to that have drugs that target the element that he identified as being part of the inflammation. The challenge there is that it’s hard to find a drug that doesn’t also affect your immune system, so we are in discussions with drug companies to see if we can find a drug that does go after this inflammation factor but doesn’t also wreak havoc in your immune system.
And last but not least, axon degeneration, is very important for 1X, as it is one of the types of CMT where we see fairly severe axon degeneration, so we are evaluating right now a proposal to actually do a specific experiment to try to highlight the role created by axon degeneration with a specific target.
Now let’s move to 1B which has about 200 mutations which fall into 3 categories, and we have good mouse models for each one of the categories of CMT1B – early onset, mid onset, and late onset. We continuing to do some testing with InFlectis at the animal level with them, and we are in the early stages of clinical planning.
By the way, if you look at the picture on the bottom left, you see three little pictures. The left one shows the myelin around the axons for a normal mouse. The middle one is a 1B mouse, so you see it’s really degraded. And on the right side is a 1B mouse treated with Sephin, so that’s why people got really excited about Sephin because it showed some really good results in the mice. And the other good news is InFlectis with their drug Sephin were recently approved for the Phase 1 trial in Europe. Phase 1 is when you actually go to healthy patients and just test the drug for safety, so if you combine this with the animal model trial we’re doing with them, pretty soon after that, it’ll be late next year, if it’s all positive, they might be able then to move to clinical trials in humans, which would be very exciting.
The other part of the puzzle is called UPR, the unfolded protein response, and because Sephin seems to be acting on this UPR, (gene makes the protein form in a different way). Dr. Mike Shy analyzed all the CMT1B mutations and figured out the ones that were affected by UPR. So those were the ones that would be most likely candidates to work with Sephin.
There is encouraging results using Sephin on CMT1A. We could potentially have clinical trials with both diseases if all goes well.
Axon degeneration is also very applicable for 1B. In fact, we funded a project which is active right now, just like in 1X, to see basically if the specific target has an effect with CMT1B. We should have the results on this probably early next year.
I put all the CMT2’s together because we find a lot of technologies now apply across CMT2s. So why is this so exciting? Basically, a few years ago there wasn’t much going on in CMT2, and all of a sudden we see a lot of activity. And this is because two interesting things are happening. The first one is all those new genetic technologies tend to apply really well for CMT2 because, if you recall, CMT2 affects neurons, and the genetic material of neurons is actually located in the spine. 90% of your neurons are in your central nervous system, so the people who are working on those technologies for the brain or the spine are very familiar with neurons, and also they’re very easy to get to and to deliver a drug to. So they really want to start to try that on CMT2s.
And the other part, based on our strategy, is that we have developed some really good models of CMT2. We have two excellent rat models which our partners really love. There’s a good mouse model of CMT2E that’s been around, and we also have some good stem cells. So all this coming together shows that there’s a lot of interest in CMT Type 2. A lot of those technologies apply across CMT2 and will carry over to CMT1, but it’s a good place to start with a lot of those new technologies, so let’s go through it.
Gene therapy. So a lot of focus on gene therapy, especially for CMT2. What we did is we put together a summit in Baltimore this summer, and it was really incredible because we asked the world experts in gene therapy to join us to help us basically not only educate ourselves but to also help us build our strategy. In the room, we had a dozen of the world’s leading experts in gene therapy. It was really amazing to see the quality of the people, their willingness to come work with us, and also the openness. They were sharing very openly, and it was incredibly productive. And basically, what we’ve been doing since then is we’ve been working with them to define a very specific gene therapy strategy, which we’re not quite ready to communicate in detail, but there’s a lot of activities, a lot of partners involved, and it’s something that’s really, really exciting to us because it will probably start in a couple of CMT2 types and may have broad applications over time across all CMT types.
And also I want to mention that there’s a family that’s done some really amazing work on CMT2D, and they are pushing a single-patient initiative. And they’ve approached us to work together with them, and we’ll support them wholeheartedly, because they’re also helping pushing the envelope.
Axon degeneration – we have an experiment going on with a partner on CMT2A that holds promise and we also have other companies that are willing to work with us on this, so very exciting.
Now, CRISPR, that’s another really interesting area. And I’m sure you’ve seen it on TV, you’ve heard a lot of the discussions about it. We’ve been approached by UCSF, and you might have seen their video about CMT, but they are really interested in working on CMT, and they really want to work with us. And they were part of our last STAR meeting. We have STAR meetings twice a year. The last one was in San Diego in October, 2018 and it was just an incredible meeting. I think all the scientists there were just glowing about how this was the best meeting ever and the quality of the new people coming in, and the CRISPR folks were there, and they really lit up the room with their ideas.
Still a bit exploratory, but fast-moving, is a technology called CRISPR surgery where you take blood samples from a given patient and then from those blood samples, they will grow them into stem cells. Those stem cells they will grow into neurons, and then they will then edit those neurons with CRISPR to remove the defective gene or fix it. And then they will reintroduce this into the body.
We also talked about the need to continue to discover new genes, especially those CMT2s, so we actually increased our funding for Dr. Zuchner in Miami, who’s doing an incredible job with his database, and he’s discovering genes almost on a weekly basis.
And then a couple of disease-specific initiatives. We actually did a screen of approved drugs for CMT2A. Unfortunately, the hits were not that convincing, so I’m not sure we’re going to follow up with that, but at least we did it, and we have a good assay to do that. And then there was a paper that came out last year that showed some specific drugs could really help with the activity of mitofusin, and we are basically doing a pilot program with them to try to dig into this further, so this could be very exciting for CMT2A. And in CMT2E, thanks to the work that was done on creating the stem cells, we are just starting to do some drug screening using those stem cells, which is very exciting.
Some people asked questions about CMT2C because the gene is the same as on some version of SMA. They were asking about the SMA drugs that has been marketed. But, again, and I’m not a specialist here, but the SMA drugs that are on the market are for a different gene than the one that is just CMT2C now. There’s some good work going on in CMT2C in a couple of centers in the U.S., and some of those things we’re talking about would apply across all of the CMT2s.
CMT4. Now, CMT4 is very well suited for gene therapy because it’s monogenic, but also because, remember, CMT4 is recessive, so both genes are affected, so there is what’s called loss of function, and this should be very attractive for people working on gene therapy because they can replace all the genes.
So we’ve had this project with Dr. Kleopa co-funded with the MDA that was actually showing some promising results in CMT4C that’s been included, obviously, in our Baltimore discussion. And then, again, there’s a family doing a wonderful job on CMT4J pushing also a gene therapy approach, and we are in discussion with them how we can work together and support them. So a lot of exciting things for CMT4 on gene therapy for CMT4, and of course, axon degeneration would apply there as well, then gene discovery as well.
We’re not done yet. We have a lot more work ahead of us than what we’ve done, so it’s really important to support STAR. And I just want to explain to you, from our perspective, why it’s so important and more important than ever to support STAR.
Leading Program – It’s a really exciting program, and a lot of partners are coming to it. Again, people speak by joining us, and the list of companies keeps growing, and there’s no better measure of success and credibility for me than this. But besides this, we’re also very careful about our resources. If you look at our financials, they’re really best in class, and we continue to improve them.
Best-In-Class Financials – If you look at most organizations, they tend to have overhead levels in the upper 20’s. CMTA historically was around 20%, which is really good, if you look on Charity Navigator, it’s actually quite good. But we’ve actually improved it. We made a lot of tough decisions the last two years because we want to continue to improve that. And if you look at last year’s financial, we were down to 12% as overhead, which is absolutely world-class, and I’m really proud of the team. And we actually think we can sustain kind of this low-teens level looking forward, so a very, very world-class performance here.
Decision Makers – And the other thing that is very special that I really am proud of about the organization is the people who are making decisions, the board members, are also major donors. So in a way, people put their money where their mouth is. About 20% of revenue comes from the board itself, so the point there is we’re going to take care of your donations very well because ours is there as well. So we are all major stakeholders here. We’re all in. We believe in it, and again, we speak with our own money and own fundraisers, and this, I think, is very unique about this organization that is very special. And I can’t say enough about my colleagues on the board and their dedication and the amazing work they do. And it’s recognized, and we work very hard for this.
Recognized: We just got upgraded to platinum by GuideStar. With Charity Navigator we’ve been in a three-to-four star range for the last few years, even though they keep raising the bar. And last year, for the first time, they gave us a perfect 100% rating on transparency and governance. We’re very proud of that, so it’s very important to look at those third-party evaluations.
Multiplier Effect – Because we work with partners, the heart of our strategy is that when we spend one dollar, it’s really to incite partners to come in and spend 10 times more at least. So when you give a dollar to STAR, obviously, we take good care of it, it’s spent very wisely, but also it brings in partners that spend the big money, and our partners spend tens of millions of dollars on CMT, and this multiplier effect is really important.
Remember, we don’t have the hundreds of millions of dollars that it takes to develop the drugs.
This is a very challenging but also very personal journey me. That’s why I wanted to show a picture of Yohan here, my little hero. He didn’t choose to have CMT, but he’s the reason why I’m involved, why we’re involved, and why we have a passion around this. And I think for all of you on the phone, I’m sure it’s the same thing. You all have a personal journey, so the point I want to make is, 10 years ago when we looked at the situation, it was bleak. It was like staring into the abyss. There wasn’t much to do. It’s not the case anymore. There’s a lot everybody can do.
Everyone can join the movement. Please get involved. Everybody has a role to play. These are exciting times, but there’s a lot of work to do, and we need everybody on board to help us.
The CMTA has branches, we have fundraisers, we have walks. Just please make CMT your cause and help us. And also, help yourself. Make sure to join the INC Patient Registry so you’ll be there when clinical trials come along. Go visit a Center of Excellence, and go again. This is how we get a natural history. It’s really important, especially for the less common types of CMT. We need more and more patients so we’ll be ready for clinical trials.
And then when I started working on nonprofits, people told me about the three W’s, and I think that applies to everybody. So we can all help through work, through wealth, and through wisdom, and hopefully all three or a combination thereof. And then all together, we’ll move this forward.
The work the CMTA is doing right now on all fronts is nothing short of impressive. Please get involved!
CMT Awareness Month Quiz – How Many Will You Get Right?
Last year, I worked on a version of this quiz for CMT Awareness month. I decided to revamp the quiz by adding a few more questions, rephrasing some of the questions and adding detailed answers. I hope you enjoy the quiz and share with others to spread awareness of CMT.
1) If you suspect you have Charcot-Marie-Tooth (CMT) disease, who would you go see?
a) A shark expert
b) A dentist
c) A psychiatrist
d) A neurologist
2) What year was CMT discovered?
3) How many people are estimated to have CMT worldwide?
a) 45 million
b) 2.8 billion
d) 2.8 million
4) CMT is a:
a) blood disease
b) neurological disease
c) infectious disease
d) autoimmune disease
5) What causes CMT?
b) the cause is unknown
c) gene mutations
6) Can someone have CMT if neither of their parents has it?
a) progresses over time
b) can, in some cases, cause respiratory dysfunction
c) May cause curvature of the spine, or scoliosis
d) Is currently incurable
e) All of the above
f) None of the above
8) CMT affects:
a) the peripheral nerves (nerves outside the brain and spinal cord)
b) the brain & spinal cord
c) the teeth and gums
d) the voice of most Country Music singers
9) Nerve damage caused by CMT can lead to:
a) muscle wasting
b) loss of sensation
d) difficulty with balance
e) all of the above
10) Common symptoms of CMT include:
a) drop foot, clumsiness, tripping
c) difficulty holding grasping objects
d) high-arched feet, hammer toes
e) all of the above
11) This is what a typical CMT foot looks like:
12) CMT can affect the thenar muscles. Where are the thenar muscles found?
13) Many people with CMT wear braces to:
a) straighten their teeth
b) protect their backs
d) correct foot deformities and foot drop
e) Show off their cool western style
14) The Charcot-Marie-Tooth Association’s overall mission is to what?
2) b – In 1886, Drs. Jean-Martin Charcot, Pierre Marie, and Henry Howard Tooth discovered CMT!
3) d – It is estimated that more than 2.8 million people have CMT, worldwide.
4) b – CMT is a disease affecting the nerves which control the muscles ( unlike the muscular dystrophies which directly affect the muscles themselves).
5) c – CMT is all about genes!
6) a – CMT can develop as a result of a new mutation or spontaneous mutation. These cases are called “de novo.” A person who has a new mutation case can then pass the condition on to his/her children.
7) – e – All the statements are true.
8) a – CMT is a group of inherited disorders affecting the peripheral nervous system, a network of motor and sensory nerves connecting the brain and spinal cord (the central nervous system) to the entire human body.
9) e – All the above. Yes, really!
10) e – CMT affects the longer nerves first; therefore, symptoms tend to start in the feet and hands and work their way up the legs and into the forearms, respectively.
Symptoms include, but are not limited to:
• Weakness in the feet, ankles and potentially legs
• Difficulty lifting the foot at the ankle during walking (foot drop)
• Depressed tendon reflexes
• Absence of development or loss of muscle bulk in feet and possibly legs
• Awkward or higher than normal step
• High foot arches (pes cavus)
• Curled toes
• Calluses and blisters on the feet
• Frequent tripping or falling
• Decreased ability to run
• Decreased sensation or a loss of feeling in feet and potentially up the legs
• Discomfort/pain in the feet
• Frequent twisting of the ankles
• Muscle cramping, especially in feet and lower legs
• Weakness in fingers and hands
• Decreased fine motor control
• Difficulty with fine motor tasks, such as using buttons and zippers
• Difficulty opening jars
• Decreased grip endurance
• Absence of development or loss of muscle bulk in hands and forearms
• Curling fingers
• Decreased sensation or loss of feeling in hands and potentially up the arms
• Overall fatigue
• Joint and/or nerve pain
• Hearing loss
• Breathing difficulties
• Sleep apnea
• Scoliosis (curved spine)
• Kyphosis (round back)
11) True. CMT feet have very high arches and hammer toes, though some people with CMT can also have flat feet.
12 e – The Hand!
13. d – Leg braces or AFOs (Ankle-Foot Orthoses) help with muscle weakness, muscle atrophy, foot drop and
14) The CMTA’s mission is to….. support the development of new
drugs to treat CMT, to improve the quality of life for
people with CMT, and, ultimately, to find a cure.
Neurologist: Well, he has CMT and yes, it gets worse over time.
Neurologist: There is really nothing much you can do about it.
Me – Silently feeling FREAKED OUT!
Neurologist: Young man, at the beginning of the game, you are dealt a specific hand of cards. Some people receive a great hand, and others, well, others get cards that kind of suck. In the end, it does not matter. Life is not successful because you hold good cards or bad cards. It’s what you do with those cards that will make or break you.
Me- Silent, trying to figure out why he was talking about a game of cards.
Neurologist: I’ll see you back here in a year.
Me: Silent, thinking that wow, we came for a diagnosis and we are leaving with an intro to philosophy.
That evening, I looked through the handouts he shared with us and I came upon the URL of the Charcot Marie-Tooth Association or CMTA. One thing led to another and I’ve been heavily involved ever since. Looking back over the past 15 years, I’m in awe of what we’ve accomplished: an abundance of CMT resources, branches, patient advocacy efforts, CMT awareness programs, and a promising research program-Strategy to Accelerate Research or STAR.
Today, I’d like to expound upon STAR.
In 2008, the CMTA launched STAR or Strategy to Accelerate Research which was innovative and unique at the time because we required scientists to work together and collaborate to advance CMT research. No more silos. No more individual superstars. No more “me” and a lot more “we”.
Since many of the genes that cause many types of CMT are known, the CMTA’s work toward finding a treatment has advanced that much quicker.
Clinical planning has started! With the Inherited Neuropathies Consortium (INC), the CMTA is developing crucial clinical infrastructures: new centers, more clinicians, patient information, and history. Get involved with CMT research: https://www.rarediseasesnetwork.org/cms/inc/
We are developing ways to measure disease progression (biomarkers) in people with CMT (this is important to see if a treatment works or not). The CMTA’s STAR has developed and is using cellular and animal models of CMT to help pharmaceutical companies test their drugs quickly.
We have partnered with pharmaceutical companies and labs to apply breakthrough genetic therapies (like gene therapy, RNAi, and CRISPR) to CMT.
Today- The Bottom Line
The CMTA currently has 25+ active research projects with top labs around the world.
Since 2009, we’ve spent over $8M to advance CMT research.
We will continue to include more and more types of CMT in our research work.
And we have forged relationships with many, many families with CMT. You will have a role in drug discovery. It’s a group effort.
All the major elements are in place and we are giving it our all to bring treatments to people with CMT. We estimate “kneading” $10,000,000 in the upcoming years to help bring CMT drugs to market. Why?
Bringing a new drug to market costs between $400 million and $1 billion. And that’s a lot of dough!
The CMTA does not have this kind of money. And I sure don’t either. But, as I wrote above, pharmaceutical companies are reaching out to us. They want to collaborate with us because our scientific work or assets are superb. In the end, they will carry the ball over the line for us. That’s why we are so excited that the number of partners has exploded in the past 2 years from a handful to about 20.
So, if you want to be part of these very exciting times:
“What’s up with the knee brace?” I asked 12-year-old Rylee, who was visiting from Pennsylvania for a couple of days. Head down, in a whisper, she told me, “My knee keeps popping out of joint. It hurts really bad when that happens. ” Just the thought of having my patella on the side of my leg for any extended amount of time makes me cringe. Yuk!
I will not stand for this. Will you?
“Ugh. Can you put these drops in my eyes?” Yohan groaned. He had just had eye surgery and needed drops every hour, on the hour. I almost said, “Buddy, you can do that yourself.” And then I remembered his tremor and weak grip strength. “I tried,” he grimaced, with water streaming off his cheeks, “but I missed!”
I will not stand for this. Will you?
I dread the thought of Bethany coming down with a cold because coughing takes energy and congestion robs her of the precious air needed to breathe effectively. Did you know that CMT can affect the nerves leading to the respiratory muscles? For some with CMT, the thoughtless act of breathing freely becomes a forced, challenging and anxiety-provoking undertaking, which may necessitate frequent visits to the ER. Not fun. Not fun at all.
I will not stand for this. Will you?
So, you see, CMT is much more than a funky way of walking, foot drop, high arches, and leg braces. CMT may also causes cramps, falls, balance difficulties, cold extremities, nerve, muscle and joint pain, curled hands and toes, altered reflexes, extreme fatigue, sleep apnea, hearing loss, etc. In short, CMT is a bitch!
I will not stand for this. Will you?
The most amazing thing about CMT is that we can fight it. Unlike many diseases, the genes that cause many types of CMT are known. The CMTA’s scientists are working tirelessly to stop or slow down the progression of CMT, and they are making headway. We’ve accomplished so much since 2008:
• Clinical planning has started. Working together with the NIH and the MDA, we are developing our clinical infrastructure: new centers, more clinicians, patient information and history over time.
• We are developing ways to measure disease progression in people with CMT.
• We are starting to use cellular and animal models of CMT to help pharmaceutical companies test their drugs quickly.
• We are partnering with pharmaceutical companies and labs to apply breakthrough genetic therapies (like gene therapy, RNAi, CRISPR) to CMT.
• We will continue to expand our program to cover more forms of CMT.
Join me to raise the funds to bring a drug to market and rid the world of CMT. Big goal? Well, maybe, but why not dream big? We’ve got to start somewhere.
WE will not stand for this.
Imagine what we can do TOGETHER! Did you know funds are what stand in the way between us and a treatment for CMT? Not scientific understanding. Not resources. Not clinics. Not patients. MONEY. I certainly don’t have all the money needed to bring a drug to market, but with your help and the help of others, the money can be raised to support scientific research. It’s doable.
Want to help? Our family has put all its efforts into Vermont’s Cycle (And Walk!) 4 CMT event and thanks to friends and family like you, we’ve raised close to $650,000 over the past 4 years. That’s not chump change, friends.
We are now preparing for the 5th Annual Cycle (and Walk!) 4 CMT event, to be held in Charlotte, VT on Sunday, August 26. Every dollar counts. Any donation is valued. Spread the word.
To join our efforts to build a better tomorrow, check out our website: www.cycle4cmt.com and donate a little or a lot.
Here is how to start changing lives:
1) Register for the Cycle (and Walk!) event and/or,
2) Fundraise! Tell others why this cause is important to you and/or,
3) Spread the word and register a friend and/or
4) Sponsor a rider, a walker or the event itself and/or
5) Sign up for the after-party.
Thank you for offering a promising future to Yohan, Rylee, Bethany and the 2.8 million + people around the world with this debilitating disease.
I’ve known Carly Siskind for at least 15 years. She is a board-certified genetic counselor who worked with Dr. Michael Shy at the Wayne State CMT clinic in Detroit (Dr. Shy’s CMT Center of Excellence is now in Iowa). Today, Carly is currently working at Stanford University and Hospital and Lucile Packard Children’s Hospital as a genetic counselor and still passionately works with people who have CMT. She’s on the CMTA’s Advisory Board, and she knows A LOT about CMT and genetics. She’s one smart cookie, so I asked her about the DNA testing company.
With all the news about potential drug therapies for CMT1A, I see a lot of people purchasing 23andMe tests to validate a CMT diagnosis. I wanted her opinion on the topic.
This is what Carly wrote,
23andMe does not look for CMT. It is approved to look at some other conditions, such as Bloom syndrome, but it does not do full gene sequencing of any conditions. In addition, it is not certified to be used for clinical actionability. If a finding is found at 23andMe, it still needs to be confirmed in a CLIA-certified ( Clinical Laboratory Improvement Amendments) lab in order to use the results for clinical purposes (such as treatment or clinical trials).
Genetic testing companies that do testing for CMT are CLIA certified, meaning that they pass government inspection of their processes and prove that they can perform the specific test with almost zero false positives or negatives (genetic testing has a 99.9% success rate). These labs also have specialized individuals who work on variant interpretation, with intimate knowledge of the genes and variants tested. The genetic testing itself is not usually the hard part – it is usually the interpretation. Having a specialized team that works on the interpretation is of vital importance to getting accurate results that provide personally and clinically meaningful results to patients and families.
Genetic testing does not need to be expensive. Check with your healthcare professionals about different laboratories that will try to make testing be a low of a cost out-of-pocket to you as possible. Many insurances will cover genetic testing, particularly if it will change management, or if for family planning purposes. You can find a genetic counselor at www.nsgc.org.
So folks, if you want to know what subtype of CMT you have, a DNA kit from 23andMe is not the answer, nor will it save you money on genetic testing. The results will not be accepted as proof of a CMT diagnosis when clinical trials are available. Genetic testing for CMT has changed. At one point, a few genetic testing companies, like Athena Diagnostics had the market on genetic testing and a full panel could cost between $15,000-$20,000. THIS IS NO LONGER THE CASE!! Please go to the CMTA website for more information about genetic testing for CMT!!
And thank you, Carly, for such valuable information!!
PS: Just to specify, I purchased a 23andMe kit quite some time ago to better understand my roots. Although my ancestry reports are quite boring – I am 100% European – it was extremely interesting to see where my relatives came from and the voyage they made. I happen to be less Neanderthal than 73% of all people who have taken the test, which made me feel good in some weird way – maybe a bit more refined (listen, it’s good for my self-esteem).
The biggest quandary I faced was to decide whether or not to look at some of the health information, including my risk for Parkinson, Alzheimer and other scary diseases. It’s like having 5 boxes, decorated in attractive glitter wrapping you go by every day. You can open them at any time, but one or all might, just might contain unsettling news – like finding out that you have a genetic variant that may increase your risk of developing certain health conditions. It’s such a personal choice. What would you choose to do? Do you want to be in the know, or not?
On Saturday, March 18, the CMTA put on a Patient/ Family Conference in collaboration with the University of Miami. We had a wonderful turnout, with people from all over the world in attendance. Gilles Bouchard, the CMTA’s Board Chair, explained progress to date on CMTA-funded research. I wanted to share my notes with You!
In 2008, the CMTA’s Board of Directors launched STAR, or Strategy to Accelerate Research. It was based on two important ideas:
Idea #1: Causes Are Known
We know the causes of many types of CMT. The big breakthrough was in 1991 when the gene PMP22 for CMT1A was discovered. Today 90 different genes have been identified as causing CMT and more and more types of CMT are being discovered each year. This is the foundation of the STAR strategy because if we know the cause of the disease, we can duplicate it in the laboratory. It is often said that “a problem that is well stated is half resolved,” and this is the case for CMT, unlike most other diseases where causes are either unknown or very complex.
Idea #2: Manage Research According to Sound Business Principles.
STAR is based on 5 core business principles:
a) Strategy: based on knowing the cause of the disease and what to focus on.
b) Our team finds the best researchers in the world and asks them to implement the projects to support our strategy, unlike most foundations who fund the best projects which are presented to them.
c) Accountability is not the most prevalent value in the world of research. We hold our researchers to their goals. We take your money very seriously. Our researchers are not fully paid until they fully deliver.
d) Collaboration: researchers still tend to work in silos. They are experts in one domain and have one focus. To solve CMT, we bring people from different fields together so that they work collaboratively. We are now seeing more and more technologies and therapies emanating from many different fields of study.
e) Partnerships: developing a new drug is not inexpensive. It costs between 400 million to 1 billion dollars to bring a new drug to market. The CMTA does not have this kind of money. We have to work with those who have the money to develop the drugs – big, strong pharmaceutical companies. In the end, they will carry the ball over the line for us.
Our Strategy. There are 5 keys elements to our strategy:
1) Assays. Assays are tests. We recreate CMT in Petri dishes. And then with high throughput screening or HTS, we test hundreds of thousands of drugs. This gives us a way to see if the medications tested have any effect on CMT. We are looking for hits. What are hits? Hits are drugs that have a positive effect on CMT.
2) Animal Models. Once we have promising hits, we then test them on laboratory animals. From millions of potential compounds, we can narrow it down to a few of the most promising compounds or drugs.
3) Stem Cells: We take human skin samples and put them through a stem cell process to create Neurons (nerve cells) or Schwann cells (which make myelin). This way, we create assays that better represent human biology. We have good models for CMT1A and have been successful with CMT type 2.
4)Partners: For CMT1A, we’ve tested millions of compounds and with the help of a major pharmaceutical company; we have several promising compounds which need to be fine-tuned for humans. With the assays, animals, and tests, we’ve created a “toolbox” for anyone who has new therapies for CMT. They can come and work with us and test them, including new technologies that may be from other domains. We can get solutions from the entire medical field. For example, 4 different drug companies who work on many different diseases reached out to the CMTA in the past couple of months alone to discuss potential therapies.
5) Clinical Trials: We are working to get ready to conduct clinical trials and develop outcome measures – how do we measure whether a drug is effective for CMT or not? See further for more details
How do we work?
We created an advisory board with top-notch researchers. The Scientific Advisory Board has 14 world class scientists. The work of STAR is not only about science, but about turning science into therapies. Another way of saying turning science into therapies is translational research. So we created the Therapy Expert Board (TEB) – a group of experts that tell us how good the science is in terms of turning it into therapies for those with CMT.
More recently, we realized we had to get ready for clinical trials and a lot of partners were coming to us for advice on how to design clinical trials and outcome measures. So we created a 3rd board, the Clinical Expert Board (CEB), where we brought together a set of world-class experts, who are helping us help our partners think about how to design clinical trials.
We have come a long way since the inception of STAR in 2008. Over the last 2 years, the CMTA has financed 40 active projects and spent 3.5 million dollars on research. We are spending your dollars wisely and in a very focused manner. We are spending 10 times more on research than when we initially started. Success breeds success. Thanks to the support from all our donors, there is huge momentum and promise.
CMTA Research Update by Disease.
CMT1A Over the past 7-8 years, we’ve done animal studies, performed HTS, got hits and worked with a company called Genzyme. Today, we’ve narrowed it down to 2 families of compounds which are being fine-tuned in the lab. Genzyme uses a traditional, small molecule pharmaceutical approach. The entire biotech industry is based on an approach where you create biological living proteins and go directly after your target.
In parallel, another company came to us with a very different approach using RNA interference. RNA interference uses little pieces of DNA to get into your nerves and affect the way the cells creates the protein which overexpresses PMP22. We’ve seen promising results in rat testing. This technology is currently used in 2 approved drugs on the market.
CMT1X is the second most common type of CMT. Researchers have identified a relationship between CMT1X and inflammation. We’ve identified the source of this inflammation and we are going after therapies to target this source. The approach comes from cancer research! Another approach is gene therapy: In CMT, there is a problem with small pieces of DNA, so you can send the right DNA via a virus into the nerves, replacing the wrong DNA. We are also investigating gene therapy for CMT4.
We have good assays and mouse models. We’ve also had several hits and potential compounds. As in CMT1X, inflammation may play a role in CMT1B, so CMT 1X research might help CMT1B.
We’ve patented a rat model and have seen promising results using stem cells. We will also complete a small screening of FDA-approved drugs this year.
We have stem cell assays and good animal models. Testing will commence soon.
Clinical Trials-How You Can Help
Every person with CMT has a big role to play. There are currently 20 Center of Excellence in the US and abroad. You can help by joining our patient registry. Clinicians need as much data on as many patients as possible to help drug companies conduct successful trials. We are also developing “outcome measures” to be able to see the effect of a drug as soon as possible so that we are able to keep the trials short and inexpensive. The traditional CMT test scores require too much time to show if a drug is working or not, so we are looking at various “biomarkers” such as fat content in calf muscles or certain chemicals in the blood.