How a Small and Young Foundation Catalyzed Research into a Rare Disease

Charcot-Marie Tooth disease is a rare, genetic nerve condition that affects 150,000 Americans and nearly 3 million people around the world. Though the condition was first medically recognized in 1886, it is without an approved therapy. The CMT Research Foundation has been seeking to change that by addressing barriers to the development of therapies for CMT. We spoke to Susan Ruediger, founder and CEO of CMT Research Foundation, about its efforts to catalyze drug development for CMT, what it’s done to address obstacles, and some of the partnerships it has established to advance the development of treatments and potentially a cure.

Daniel Levine: Susan. Thanks for joining us.

Susan Ruediger: Thank you, Danny, for having me, it’s quite an honor to be here with you.

Daniel Levine: We’re going to talk about Charcot Marie Tooth, the CMT Research Foundation, and how a small foundation can catalyze and advance research into a rare disease. Let’s start with Charcot Marie Tooth disease, which is not a dental condition. What is CMT and how does it manifest itself and progress?

Susan Ruediger: CMT is genetic peripheral neuropathy. It’s a progressive disease that affects the nerves in the peripheral nervous system, anything outside of the spinal cord. It’s genetically caused and there are over a hundred genes that are known to cause it, and it’s progressive. It starts in your toes and in your fingers, and then it slowly works its way in toward the center of your body. It can cause pretty mild disability in some people and in some people it can prove to be fatal. It’s a wide spectrum of disability but certainly one that leads to daily frustrations for patients and can be very demoralizing to watch your body progressively lose the function that you used to have.

Daniel Levine: We think of the complexity of developing therapies for single gene disorders. How complicated is it to get a diagnosis or develop a therapy for a condition where so many different genes might be implicated?

Susan Ruediger: That’s a great question. The good news is that there are four genes that are implicated for four of the most common types of CMT. Four genes are responsible for 90 percent of the people who have CMT, and one gene is responsible for over 50 percent. The good news about CMT is they’re all monogenic diseases, meaning that only one gene defect is causing the disease, but they’re just a hundred different known genes now and many more that are yet to be identified. We do have good news that 90 percent are caused by one of four genes and good research has been done on that. So, applying gene therapy to one of those four types, there are efforts underway right now for that. For some of the rarer types, there are good efforts underway because of the severity or because of the relative ease in addressing it genetically.

Daniel Levine: What’s it like to live with this condition? How does it impact daily living?

Susan Ruediger: It is so frustrating, Danny. I have CMT as does my partner and co-founder Pat Livney. So, we’re founded by patients because we understand how frustrating this is. As a child, I tripped all the time, I knew I was physically different, I couldn’t walk on the balance beam, I couldn’t jump on a trampoline, I couldn’t keep up with my friends when we were playing cops and robbers in the streets, I was always first out in dodgeball, and last picked for the sports teams in PE class. That was my experience when I was little. As I’ve grown older, I started falling more often and didn’t know why. I went to college on a large college campus and fell on a regular basis just from being tired from walking across campus. Then, I needed leg braces to keep me from falling, then watching my hands deteriorate, fastening necklaces has gotten harder. I know the progression that’s coming. I remember standing up on my tip toes to grab something off the top shelf in the kitchen, for example, and I can’t do that anymore. I come from six generations of people who have CMT. I can look at my mother, who is mostly in a wheelchair and sometimes in a walker, and I know that’s my future. I know where the progression has gone in my family. So, there is this impending fear of lack of independence. It can be very frustrating daily because I used to be able to reach that thing on the top shelf or I used to be able to fasten my necklace and today I can’t. Then there’s also that cloak of fear of what’s coming in the future. I kind of consider myself to be one of the lucky ones, Danny, because I have CMT 1A, which is considered [one of] the more mild types. In some types, people have difficulty breathing, hearing, seeing, and they have tremendous nerve pain and it’s progressive. I know a handful of people who have passed away from the progression of CMT impairing their ability to breathe.

Daniel Levine: This is a condition that was first medically recognized in 1886, a hundred thirty-five years ago. Yet, there’s no approved therapies to treat the condition, even though it is among the most prevalent rare diseases. Why is that?

Susan Ruediger: It’s a great question. I’ll tell you that the first gene was identified 31 years ago for the most common type, CMT 1A, the type that I happen to have. So, why 31 years and we don’t have treatments yet? I think there are a number of reasons for that. One is there are some real key barriers pharmaceutically to treating a disease like CMT. For example, how do you reach the peripheral nervous system, how do you deliver a drug to every teeny, tiny peripheral nerve, how do you measure efficacy in a slowly progressive disease, and is it possible to regenerate nerves that have already died? These are questions that we’re working on answering scientifically. There are big questions that there isn’t a demonstrated proof of concept for. So, maybe the pharmaceutical companies don’t want to take that on. I think the other piece that can be very frustrating from the patient community is the lack of awareness about CMT and its severity within the medical community, within the patient community, and within the pharmaceutical community. To give you an example of what I mean, when I first was diagnosed genetically with CMT, it was about 17 years ago. My neurologist, who’s one of the leading neurologists in my town, said, “Sure, you have CMT, what do you want me to do about it, I can’t do anything about it so go live your own life.” So, I think that flippant mentality of—this isn’t the worst disease I see coming across my doorstep and there’s nothing I can do for you, so go live your life—gives  this hopelessness that patients have and also creates a lack of interest from the medical community. Then I think the pharmaceutical industry has looked at CMT historically and says, you know, it’s not killing people, it’s mild, and they’re diseases that are far more severe that will require our attention earlier. I think really that nobody’s strongly shown a light on the importance of CMT. This is one of the reasons why Pat and I started the research foundation because we know that there’s this lack of awareness and this lack of interest and we are here to change that.

Daniel Levine: When you started the foundation, what was the intent?

Susan Ruediger: To deliver treatments and cures for CMT. We have one single focus at the research foundation and everyone who works with us—our board, our scientific advisory board, our staff, and our volunteers—we’re all focused on one thing and that’s funding research that’s going to lead to treatments and cures for CMT. That was our original intent and it remains our single focus. It’s the only reason why we exist.

Daniel Levine: How did you go about putting together a research strategy and what is the research strategy?

Susan Ruediger: Thank you for asking that question. Our research strategy is clear. It’s what are the key barriers to drug development for CMT and how can we as an organization overcome those barriers? Why do we not have treatments yet? That was the question Pat and I asked each other and then our board. Then we found scientists in the CMT community, in the drug development community, and in the clinical community who could help answer those questions. Now, we’ve identified four key barriers in drug development for CMT, and we have strategies to attack all four.

Daniel Levine: Walk me through those. What are the biggest barriers you face?

Susan Ruediger: The first one, we already talked about, is how to deliver drugs to the peripheral nervous system. If we’re talking about a gene therapy, what we’re seeing in other diseases, like spinal muscular atrophy, is that the gene therapy is being injected into the spine and it’s transducing throughout the entire spine, which is terrific and becoming curative for those kids. How do we get a therapy into every tiny peripheral nerve in your fingers, toes, legs, arms, et cetera. That has been a key barrier that we’ve identified. The way that we’ve attacked it is by finding partners who focus on delivering gene therapies and saying, can you apply that focus to CMT? Let me give you a couple examples for that. I went to a meeting with Chris Austin, who was then the director of NCATS over at the National Institutes of Health, and I said to him, “it’s a big problem overcoming the delivery of a therapy to the peripheral nervous system.” Dr. Austin told me to go to James Dahlman at Georgia Tech, he is one of the very best in delivering gene therapies to different systems in the body, and talk to him about how to deliver to the peripheral nervous system. We talked with him and our scientific advisory board met with him. We designed a project, we provided funding, and we started that with Dr. Dahlman. So, it’s knowing exactly what our barrier is and finding all of the people who can work on that. That’s one of the key barriers for drug development in CMT. Another one is this problem of addressing a hundred different genes known right now, and then hundreds of mutations in some of those genes that cause CMT. Are we going to have to deliver a genetic therapy for each individual mutation? That could be hundreds, maybe even thousands of different precision individualized medicines. Instead, are there learnings we can take from other genetic diseases that we can apply to CMT that have broader relatability to either one whole gene and all the mutations in that, or even multiple genes. Are there ways that we can knock out and replace genes with the right thing, one therapy that can address those types. Instead of showing a pharmaceutical company hundreds, or maybe thousands, of different approaches, showing them a handful and showing how that could have broad appeal to larger groups.

Daniel Levine: How is your organization funded and what do you do to get the biggest bang for your buck?

Susan Ruediger: Our organization right now is solely funded by the donor community. What we’re finding the donor community to be is mostly the patient community, patients, families, people who have this very close connection to CMT, and people who understand the burden of living with CMT and want to end the legacy that they may have given to their children or to their grandchildren. Those are the people who are most inspired right now to make donations to the research foundation for us to then allocate funding. That’s how we’re funded. I think your second question was how do we make get the biggest bang for our buck?

Daniel Levine: Yeah. How do you maximize the return on what, I imagine, is a limited pool of investment you’re working with?

Susan Ruediger: It is a limited pool of investment. One of the things that we’ve been able to do is provide seed funding to key partners and then have them raise more money for CMT. Let me give an example to you to put that in real world [terms]. Back to the delivery issue, we identified a company, DTX Pharma. We found them at BIO, an international conference of pharmaceutical companies. DTX focuses on delivering gene therapy to different systems. We pursued them, had a meeting and said, does your technology apply to CMT? They met with our scientific advisory board and said yes, it does. We gave DTX Pharma, $125,000 in January of 2019. Eight months later, DTX Pharma received a grant from the NIH to continue the same CMT project for $350,000. Then six months later it closed a series B round of financing for $100 million with CMT being one of two lead indications. They would never have started a CMT program if we hadn’t introduced them to the disease and given them the seed funding. Because of that seed funding, their data was so good because their technology was so well suited for CMT, that they were able to raise a hundred million plus. Now their commitment is to take their drug all the way through to clinical trials. That’s what we do, we’re catalytic funding. That was $125,000 of donor money that is now preparing for clinical trials.

Daniel Levine: You’ve also gotten involved in a potential gene therapy work you’ve done with researchers at the Cyprus Institute of Neurology and Genetics and Nationwide Children’s. What happened there?

Susan Ruediger: Dr. Kleopa is well-known in the CMT world. He trained at U Penn in the CMT clinic and he went back to his home country of Cyprus and brought that training with him. He was funded by other organizations to start two other CMT gene therapy programs. I met him at a meeting, congratulated him on his work, and asked him why not CMT 1A? You’re focused on these other types, why haven’t you applied your technology to CMT 1A? He said it’s a matter of funding and because we’re using an AAV we’re not sure that CMT 1A is aggressive enough to get an FDA approval for use of an AAV, and we’re not sure that that’s a risk worth taking. I said, write a proposal and let’s see what it comes back as. One hundred grand is what we gave them. Dr. Kleopa collaborated with Scott Harper at Nationwide Children’s, which is one of the best in the gene therapy world, and they worked together to build the right gene therapy, build the right delivery mechanism, test it in the right models of CMT 1A, and now they are preparing to have that licensed by a biotech and preparing that for clinical trials.

Daniel Levine: I want to ask you about the relationship you forged with AcuraStem. How did that relationship come about and what are you seeking to do there?

Susan Ruediger: AcuraStem has this really interesting technology where they’re taking patient derived stem cells and they are turning them into motor neurons, then testing different drugs on whether they increase the survival of the motor neurons. Many types of CMT, anything that’s labeled CMT type 2, is a motor neuron disease. All the CMT type 1’s eventually lead to motor neuron loss. So, that’s really what causes all of our symptoms. If there’s anything that we can do to make those motor neurons survive longer, that would be a therapeutic to us. It would lengthen our time of higher ability or shorten our time of disability if you will. We used patient derived stem cells, which were blood and skin, and we had them differentiated into motor neurons. In one project with AcuraStem, we are testing approved drugs and well-established libraries to see if any of those drugs lengthen the survival rate of these motor neurons. That’s for CMT 2A. Again, AcuraStem had never heard of CMT before we came to them. They were focused on ALS and focused on the motor neuron survival there. We said, is this relevant to CMT? How can we make it so, and how can we get you guys started on CMT? It was expertise from our scientific advisory board and funding from our donors that brought that together and made that happen.

Daniel Levine: You talked about the way you can leverage your investment by catalyzing research. There’s actually, at this time, a fair bit of commercial interest in CMT. There a pipeline of something on the order of 20 plus therapies in development. As you move away from needing to catalyze research, are there other ways you can support therapies and development?

Susan Ruediger: We are definitely familiar with all the companies who have assets in the pipeline. We’ve had conversations with them and asked what are their barriers and how can we help. In some instances it’s expertise, in some ways it’s funding, in some ways it’s letting them do what they need to do. If you’re talking to me, a patient who has CMT and knows the very low success rate of drugs under development, I look at a pipeline of 20 and I say that needs to be 200 or 2000.

Daniel Levine: You’ll be hosting the first global conference on CMT in Alexandria, Virginia in September. What do you hope comes of that?

Susan Ruediger: What we really hope that does is bring the entire global community together because CMT is a global problem. We didn’t talk about this, but it’s found on every continent. Three million people in the world have CMT. From the best we understand it’s found in every ethnicity. Global problems require global solutions. This international conference will bring together the global research community to address these key problems and to share the knowledge that’s out there and to say, what are the barriers that we’re having, who in this room has solutions to those barriers and how can we collectively overcome those barriers. So it’s taking what we’ve done at the scientific advisory board, which is about 15 people and expanding it to the entire global community. CMT is really well studied in China. It’s really well studied in Korea. It’s really well studied and in Australia and in Europe. How can we bring all those voices to the table with an open invitation to address and attack this problem so we can have treatments?

Speaker 2: Susan Ruediger, founder and CEO of CMT Research Foundation. Susan, thanks as always.

Susan Ruediger: Thank you, Danny. Appreciate it.