How One Patient Organization Catalyzed Drug Development

Monica Coenraads, the mother of a daughter with Rett Syndrome, has played a critical role in catalyzing development of therapies to treat the rare, neurological disease. She co-founded and served as director of research for the Rett Syndrome Research Foundation. She later founded and today serves as CEO of the Rett Syndrome Research Trust. Her work shows how patient organizations can bridge the translational divide and de-risk rare disease drug development for biopharmaceutical companies. We spoke to Coenraads about her experience with Rett syndrome as a mother of a daughter with the condition, how she crafted a scientific agenda for the organizations she founded, and what other rare disease organizations can learn from her experience.

Daniel Levine: Monica, thanks for joining us.

Monica Coenraads: Thank you very much for having me.

Daniel Levine: We’re going to talk about Rett syndrome, the Rett Syndrome Research Trust, and how you’ve been able to play a critical role in the translation of academic discoveries to therapies and development by industry. Before we talk about your work, I’d like to start with your story. When your daughter was two years old, how did she come to be diagnosed with Rett syndrome?

Monica Coenraads: Yes, so she was our first child. We had been married for almost 10 years. I owned a restaurant at the time and was working crazy hours and we had decided to put off starting a family, and so she was awaited—a very awaited little baby, first grandchild, both sides of the family. The first, I would say seven or eight months, nine months seemed perfectly normal, and then there started to be some signs that she wasn’t picking up new skills or learning things—hitting her milestones by a year old. I was very concerned. She wasn’t pulling up to standing, she wasn’t learning how to crawl. She started dropping things from her hands that she previously was able to hold, so there were a number of disturbing signs. We were going to the doctor. They were all telling me that I was to wait. Children develop at different speeds and hold on, she’ll catch up, but she didn’t catch up and by 14 months we started doing some therapies. We saw a developmental pediatrician. We were going to neurologists. No one had brought up Rett syndrome. I found Rett syndrome on my own. I was on a listserv of moms who had all had babies in October of 1996, and one of the moms said to me, look up Rett syndrome. My neighbor has a child with Rett. Look it up and see if any of the symptoms resonate with you. And they did more than resonate. I was going down the list and saying, oh my gosh, I think we found what my daughter has. I went to the pediatrician the next morning, got there before she did. I didn’t have an appointment. I just showed up early in the morning. She had remembered maybe hearing about it in med school, but had never had a patient with it. We were living in Northern Virginia at the time. There was a Rett syndrome clinic at Johns Hopkins. We made an appointment. This was before there was a gene, so there was no blood test and they weren’t used to seeing children so young at the time. She was about 20 months old, and they said, come back in six. I was like, how am I going to get through six months? It was just a very scary period. Anyway, she started developing more of the symptoms and on her second birthday or close to it, she was clinically diagnosed with Rett. A year later, the gene that when mutated causes Rett syndrome was discovered, and I already had her blood and all of the labs that were looking for the causative gene. And so, I found out very quickly that yes, she did have a mutation in this gene, and so then the clinical diagnosis was confirmed with a genetic diagnosis.

Daniel Levine: How does the condition manifest itself and progress?

Monica Coenraads: It’s typically diagnosed in girls. It’s rare in boys, although boys can also be diagnosed with Rett syndrome, but the majority of patients are girls. The first year is fairly normal, and then there’s a plateau where skills are lost or not gained. There’s typically a regression phase, so children lose hand function. If they have words, they stop using them. They don’t learn new ones. There’s gross motor problems. If they’re walking, about 50 percent of the kids can walk, but they have a very stiff gait. The other 50 percent never learn to walk. So there’s a host of problems. And then as they get older, many of them develop seizures. There’s breathing abnormalities, breath holding, hyperventilation, gastrointestinal problems, muscular skeleton problems, sleep problems, anxiety, I mean on and on and on. And my daughter’s 27 now, she’s in a wheelchair, unable to speak, has no purposeful hand use whatsoever, seizures, fed through a feeding tube. So it’s a very debilitating, serious disorder that affects quality of life for her definitely and for the family as well.

Daniel Levine: It seems like you were ahead of your physician on this, but what were you told when you eventually got a formal diagnosis?

Monica Coenraads: Not much. And you’re right. At that point, I already knew more than they did, and this was ‘98, ‘99, there was information online. I was able to access some journals and articles and just basically educated myself. Yeah, there wasn’t that much known. And what was known was very depressing.

Daniel Levine: You co-founded the Rett Syndrome Research Foundation in 1999, a year after your daughter was diagnosed. What was the vision for the foundation?

Monica Coenraads: Well, I’m not sure I had a vision at the time. I didn’t start out deciding that I wanted to start a foundation. What I did was first you get this horrible news that your baby has this rare, debilitating lifelong disability. And then when you start researching Rett syndrome, you find out that at first there was no cause, right? A year later, yes, we found the cause, but there was very little research being done and certainly no drug development. Industry barely knew what Rett syndrome was, let alone anybody actually pursuing it as a disease indication. So, at first I was like, okay, what can I do? I’m not a physician, I’m not a scientist, I’m not wealthy. What can I do to get things moving? And it was one phone call led to another, one introduction led to another, and slowly I started to piece together a plan of how to move research along. I found some like-minded parents who felt that research was incredibly important, and we got started. I didn’t know much at the time. When I look back now and I think about some of the people that I called and how little I knew, I actually get butterflies in my stomach about how naive I must have sounded. But one thing I will say is that every scientist, every clinician that I spoke to was empathetic, was kind, was helpful, treated me with respect, and helped me. And I had a lot of mentors, a few key ones who taught me. I read voraciously. It would take me a long time to get through papers with a medical dictionary and looking up scientific words that I didn’t understand. I bought a coloring book about the brain—an adult coloring book that taught you about the brain and the different parts of the brain. And so, just self-taught basically.

Daniel Levine: I should note, you were scientific director of the organization for eight years. I think many patients may be intimidated and family members of patients may be intimidated when they think about educating themselves about drug discovery and how these complex diseases work. How big a learning curve was there, and do you have any advice you would give people on how to tackle this?

Monica Coenraads: Well, I am still on that learning curve. I learn something new every single day, and I often tell people that I’m operating out of my comfort zone 24 hours a day. That’s just the nature of what I do. But I’ll also say there’s been some benefits, I think, to not having a scientific background and coming to this with more of a common sense, not being biased in any way for or against any kind of therapeutic modality. Sometimes that’s been helpful. I think it’s also allowed me to ask a lot of direct questions that maybe I wouldn’t have gotten away with had I been a peer to some of the people I was talking to. So there has been benefits, but I think for parents that are trying to do the same thing for their child’s disorder, don’t underestimate the time that it’s going to take. And I was able to thankfully be able to do this full time from the get-go. I think of parents who have to do another job, and it’s hard. It’s not something that you can really kind of do. I think if you’re going to be good at it and be successful, it’s going to take a lot of time, but it can be done. And I’ve met tons of families like me, tons of parents like me who’ve learned the science, who’ve learned the lingo, and you don’t do it alone. You’re not doing the drug discovery alone. You’ve got mentors, you’ve got advisors. I’ve got a staff now that knows a lot more than I do about drug discovery, so hopefully they’re not doing it alone. I certainly didn’t.

Daniel Levine: The Rett Syndrome Research Foundation today is the International Rett Syndrome Foundation. It’s the result of a merger between the foundation and the International Rett Syndrome Association. In 2008, you founded the Rett Syndrome Research Trust and serve as its CEO. Why was the trust needed? How does its mission differ from the International Rett Syndrome Foundation?

Monica Coenraads: So, the Rett Syndrome Research Trust, the organization that I run now, launched in 2007 on the heels of a remarkable paper that was published in 2007 by Adrian Bird, Sir Adrian Bird actually, and he’s a pivotal figure in our field. Adrian discovered the MECP2 gene in the early nineties. He made the first animal model. Much of what we know about MECP2 function comes from his work. And he came to me in, I think it was around 2003, with an idea for a very bold experiment. He would generate a conditional knockout mouse, a mouse model where you could control when the gene is on or off—MECP2, that’s the name of the gene involved in Rett, and he wanted to create a mouse that had no MECP2, let it develop all of the Rett symptoms, and then turn the gene back on and see what happens. He submitted a proposal to my organization and we funded it. It was a three year project, and I lived through all of the ups and downs of that project, but the end result was really worth it, and he was able to publish in 2007 and showed that when MECP2 was turned on, every symptom that was measurable in a mouse model went back to normal or near normal. In other words, Rett syndrome was reversible, at least in mice. This shocked the scientific world because it suggested that severe neurological disorders were not beyond repair, right? And Adrian often said to me that if he was a neuroscientist, which he’s not, he might never have done that experiment because existing dogma suggested it wasn’t worth doing. The result wouldn’t be what we would hope for, and thank goodness he’s not a neuroscientist. But that result changed everything for me. And from that moment on, I really wanted to focus 100 percent on genetic medicines with no distractions. And I launched the Rett Syndrome Research Trust to do that, and Adrian joined me as a trustee, and 17 years later, he’s still a trustee and a trusted advisor.

Daniel Levine: As you started this new organization, how did you go about crafting a research agenda?

Monica Coenraads: Yeah, so we did kind of do things differently than we were doing at the first organization. The first organization, keep in mind that we were trying to fertilize the field back then, right? Very few people were working on Rett, and so we were doing RFPs and doing what most disease organizations do. The RFPs come in and you get them peer reviewed, you prioritize them, you fund what you can afford to fund. When I started our Rett Syndrome Research Trust, RSRT, we took a different approach. Knowing that we had a genetic medicine focus, we identified all of the areas that we wanted to be active in. So, in the beginning it was gene therapy, and we also started doing some work in epigenetic editing, trying to reactivate the silent MECP2. As discoveries came about, we added to those modalities. In 2016 after David Liu’s base-editing paper, we added a base-editing modality, then we added prime editing, then we added RNA editing. So, our focus was really to leave no stone unturned. Let’s pursue every modality where the focus is increasing levels of MECP2. That’s what we need to do. There’s multiple ways to go about doing that, and that was our strategy—focus on genetic medicines, every modality where we can boost levels of MECP2. I started hiring an internal team as well, a chief medical officer, then a chief scientific officer, and then a year ago we hired a chief technology officer. They’ve got a lot of drug discovery business development experience, and that’s really been a game changer to put together an internal team so you’re not just relying on advisors. And so, the strategy has changed over time. We also have clinical research efforts that we’re pursuing—patient registries and digital natural history studies, and we make sure that we kind of check all the boxes of all the resources that companies are looking for when they’re trying to decide whether to enter the Rett field or not. Is there patient information? Is there a natural history study? Are the animal models available? Do you have a biorepository of patient cell lines? The more we can check, the more likely that a company might be more willing to get involved in the field.

Daniel Levine: Well, the organization has been successful at raising money to fund research. How much have you been able to raise and what’s accounted for that success?

Monica Coenraads: So, we’ve just crossed the hundred million mark, and that’s been since 2008. I think what’s accounted for the success is families who are willing to step up and get involved in fundraising. We can track every dollar that we’ve raised back to the efforts of a family that has an affected child. So whether that’s through events or crowdfunding or connections to a philanthropist or a foundation, whatever it might be. But we don’t get random donations from people that don’t have an association with Rett syndrome. We don’t get government funding. We don’t really get corporate funding. So it’s really grassroots efforts from families.

Daniel Levine: And you talked about things like registry, natural history study. How did you go about prioritizing what you needed to do to lay the groundwork for the development of therapies?

Monica Coenraads: Well, fortunately, I had team members that have experience in this area. Our chief medical officer, for example, has started companies that were active in the neurodevelopmental space, had a lot of experience dealing with patient advocacy groups and kind of knew what we needed. And our chief scientific officer has lots of experience in clinical operations. And for example, it was her idea to have a biorepository of patient cell lines. There’s lots of labs that have developed cell lines with mutations, right? Patient mutations. But it’s very difficult for companies to get access to those lines, not because the investigators don’t want to share, but because the MTA offices and their universities make it difficult, unfortunately, to do so. So we decided to start our own, and it’s not cheap to do that, and it took time, but we’ve had over a hundred requests now for patient cell lines from our biorepository. So that was something that was really critical and formed the basis of certain companies being able to pursue a lead program in Rett syndrome.

Daniel Levine: At what point did you have discussions with drug developers and what led to their interest in pursuing therapies?

Monica Coenraads: So I guess that started in 2017, 2018, 2019. Some of the first discussions happened when the data from our gene therapy consortium that we had started, they started to generate preliminary data that looked very encouraging. And what started off as academic programs were transitioned to companies. There’s now eight companies that have publicly announced genetic medicine programs for Rett syndrome. Some of those were funded by us. Some of those started in programs that we were funding at the academic level, and then were transitioned to companies. So there’s lots of discussions with companies now. I mean, just today I had two meetings with companies. So now of course, it’s all companies that are focused on genetic medicines—they either have a Rett program, they’re exploring a Rett program, we’re doing outreach maybe because they have a technology that is interesting and relevant, and we’re introducing them to the RETT space. Fortunately, I used to have to start my conversations always explaining what is Rett syndrome. That never happens anymore. Everybody knows what it is. They may not be up to date on the latest paper, but they know, roughly speaking, what’s going on in the field. And that’s been a huge change. But I do a lot of outreach to companies also in the delivery space because all of our programs are in need of a delivery technology that allows the cargo, whatever it is we’re delivering to get into the brain in a diffuse manner. So we’re paying a lot of attention to what’s going on, viral delivery, non-viral delivery, having a lot of conversations with companies around their delivery technologies

Daniel Levine: With multiple companies pursuing therapies or having interest in the area. Is there any pre-competitive collaboration going on?

Monica Coenraads: Yes. And I think areas where that tends to happen is, for example, biomarker discovery work or outcome measures. These are areas where all the companies would benefit from having a biomarker or having outcome measures that are objective. And so those are areas where we’ve started collaborations, pre-competitive collaborations. We don’t force anyone to sign anything; it’s just come share your knowledge. We’re not forcing you to do anything that’s uncomfortable. And let’s see what comes out of it.

Daniel Levine: In 2023, Acadia Pharmaceuticals won approval for the first therapy for Rett syndrome. This was approved on the basis of a set of clinical scores intended to measure improvement in symptoms. It’s not understood how the drug works. How significant a development was this for the Rett syndrome community?

Monica Coenraads: So there has been significant interest in the drug in the Rett community, and rightly so, given the severity of the disorder and the lack of treatments. I think the approval’s been significant in that it has shown the biopharma community that there’s a regulatory path forward for Rett syndrome. It showed them that trials can be conducted for this rare disease. It has shown investors that a drug can be commercialized. I think it’s raised the profile of Rett syndrome at the FDA and the profile of Rett in general. So those are all good things. You mentioned that the approval was based on clinical scores, and that’s indeed the case. The outcome measures were rating scales, right? One that parents were asked about and one that clinicians filled out. There were no symptoms that were actually measured in patients, but rather parents, clinicians were asked to interpret how they felt their child or the patient was doing. This isn’t surprising. It’s the norm for outcome measures for neurological disorders, but the scales are subjective and they’re vulnerable to placebo effect. So one of the goals at RSRT is to develop objective outcome measures where we’re actually measuring symptoms in a quantifiable way in patients, and we’ve done some pilot work in this area. We’re about to launch a study called Vibrant that’s going to test a number of wearable devices, including what’s called an invisible device, a box that sits in a room, kind of like your wi-fi box, and collects physiologic data from radio waves that reflect off the patient. And we’re going to be measuring sleep and breathing and starting to characterize movement. And this is an area that companies are very interested in. Our CSO, Jana Von Hehn, just wrote a great blog about this on our website, was published this week.

Daniel Levine: Is protein expression a viable biomarker for this?

Monica Coenraads: It’s hard to do. It’s hard to measure protein levels. We would need to measure them in the brain and even in the spinal fluid. It’s very tough to do so I think that’s going to be a tough biomarker. We’re looking at molecules in blood that track disease severity for biomarkers that are not clinical outcome measures.

Daniel Levine: As you see drugs that are targeting the underlying molecular mechanism of the disease, how quickly do you see therapies advancing in changing what it means to have a Rett diagnosis?

Monica Coenraads: Well, I think we’ll start to get some clues fairly soon. There are two industry-sponsored gene therapy clinical trials that are ongoing now. One is sponsored by Taysha Gene Therapies and the other one is Neurogene. By the end of the year and first half of next year, we’ll start to get some results on the first patients. And so I think we’ll start to get a clue about what symptoms improve and by how much and does the age matter? Does the severity matter? Does the type of mutation matter? Of course, these trials using these programs are using AAV9 as a viral delivery technology. So, we’ll also maybe get some clues about how well AAV9 is working for Rett. Both companies are using different routes of administration. We’ll be able to start to get a clue about what route of administration is better. So, I think the next six to nine months are going to be really interesting. Beyond that, we just launched what we’re calling Roadmap to Cures. It’s our strategic research plan. Our goal is to select three genetic medicines beyond kind of traditional gene therapy. So we’re looking at editing approaches to start IND enabling studies next year and hope to be in clinical trials by 2028.

Daniel Levine: Do you have any sense of how genetic medicines might benefit older people living with the condition, or is it only expected that these will really change the course of the disease for people who are newly diagnosed?

Monica Coenraads:

Well, I’m hopeful that it’s going to help every patient regardless of age. The reason I’m saying that is from an animal model perspective, you can take a mouse that’s never had MECP2, a mouse model of the disease, and put MECP2 back at any stage—prenatally, at birth, later on—and that mouse recovers. The symptoms reverse. Now a mouse is a mouse, and we’ll have to see what happens in people. But brain cells in people with Rett syndrome don’t die. They’re all there. They’re all in the right place. And so we’re hopeful that we’ll be able to improve the symptoms regardless of age. Now, do I think that intervening in a one-year-old is going to be better than intervening in a 30-year-old? Yes, of course. I think the earlier the better, and eventually, maybe this is an intervention that’ll be done in utero, and these kids will never develop any symptoms at all. But I do have hope for older patients as well.

Daniel Levine: What advice would you offer other patient advocacy organizations looking to advance therapies for their conditions? What can they learn from your experience?

Monica Coenraads: Well, I had so many mentors along the way, and so I’m really grateful when I have an opportunity to share what I’ve learned and pass it forward. I’m contacted almost every week by parents of children who’ve been diagnosed with one genetic disorder or the other, and eager to kind of do what we’ve done at Rett Syndrome Research Trust. So, a few things that come to mind is all those building blocks that I mentioned before, the registries and natural history studies, the biobanks, the animal models, get those in place as soon as you can. Make sure that the mouse models are freely available. And it’s important, I think, that it’s nonprofits that spearhead these efforts because if it’s a company, they’re going to keep that information proprietary. And so, it’s important that it’s nonprofits that do this work. I think it’s never too early to think about genetic medicines. I would recommend that they try to hire somebody with industry experience early on, and I know that that can be expensive, but maybe there’s a way to do it or that disease groups that are small can perhaps share a person. But I have found that it’s been a game changer for us. I think one piece of advice I would give is don’t fall in love with the science that you fund. Try to always really be objective. Fund people that are collaborative. And from a fundraising perspective, because of course, always, you can’t do anything if you don’t have money. And that’s hard because a lot of the people that are contacting me, these are super rare or these are genes that nobody knew much about, and so, there’s 10 people diagnosed, 20 people. It’s hard to fundraise when you have such small numbers, but I have found that it’s easier to fundraise when you have a plan in place and then you’re not raising funds for something vague, but you’re actually raising funds for something very tangible. And so, get together with your scientific advisors, or if you’re lucky enough to have a person on staff and put a plan together.

Daniel Levine: Monica Coenraads, founder and CEO of the Rett Syndrome Research Trust. Monica, thanks so much for your time today.

Monica Coenraads: You’re welcome. This was fun. Thanks.

This transcript has been lightly edited for clarity and readability.

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