RARE Daily

Turning Grief into Action

October 19, 2023

The Yaya Foundation recently achieved a milestone in advancing towards treatments for 4H leukodystrophy when it successfully developed a mouse model. It reflects a broader effort that has allowed the organization to drive towards the development of a gene therapy to treat the rare, neurodevelopmental. We spoke to Ron Garber, co-founder and board president of the Yaya Foundation, about 4H leukodystrophy, how the organization built a research agenda, and the rapid progress it has made.

Daniel Levine: Ron, thanks for joining us.

Ron Garber: Danny, thanks so much for having me. I love your podcast and I’m really excited to join you.

Daniel Levine: Thanks. We’re going to talk about 4H leukodystrophy, the Yaya Foundation, and a recent milestone it achieved with the development of a mouse model for the condition. Perhaps we can start with the condition itself. What is 4H leukodystrophy?

Ron Garber: Yeah, 4H leukodystrophy or POLR3-related leukodystrophy, as it’s also known, is a disease of myelin in the brain, and in our neurological system. And it’s genetic neurological disease that’s auto recessive, so we inherit it via our parents. If our parents are a carrier of a genetic difference that leads to it, we have a one in four chance of being affected by the disease. And it effectively means that for people who are affected, they don’t develop myelin properly during a critical phase of development. And that leads to all sorts of different problems, which are different for different people because it’s a really heterogeneous disease, highly variable phenotypically, and that can be confusing to our patient community. And it was confusing to my family at first because everyone who was affected by the disease presents differently. But at its essence, people who are affected develop regularly at first, and then at some critical point in time, in typical 4H around two or so years of age, start to develop symptoms. And that starts usually with motor issues and muscle tone issues and just problems with mobility generally. There’s often abnormal tooth development, so our patients don’t develop teeth at all or develop them late and often when teeth do come in, they’re shaped differently. And later in life there are endocrine symptoms. So our kids have delayed puberty or sometimes no puberty at all. And then ultimately respiratory and feeding issues. And all of that sort of declines over time, slowly in the case of normal 4H, rapidly in the case of my daughter’s condition and other patients like her. And sometimes, we’re learning, really, really slowly for people who are affected by the disease and live well for a long time, but then have motor issues show up later in life. So very different for different people. But that’s 4H leukodystrophy in a nutshell.

Daniel Levine: You were thrust into the world of rare diseases when your daughter Yaya was diagnosed 4H leukodystrophy when she was just eight months old; she died at 13 months. How did she come to get diagnosed and what were you told about the condition when she was diagnosed?

Ron Garber: Yeah, it’s a great question because eight months and 13 months—it doesn’t seem like a long time, but it’s a lifetime literally. And it certainly felt like a lifetime then. So, I’d love to just talk about Yaya for just a moment, just as a person. She was our firstborn. She was a lovely little kid. When we came home from the hospital, we were just tired, happy new parents, didn’t know that anything was wrong, and Yaya was just a really special kid. She was loving, sweet, she loved being kissed on the cheek. You would kiss her on the cheek sort of rhythmically, and she would kind of act like she didn’t like it and look away and play hard to get. But then if you didn’t do it on the rhythm, she’d look back like, Hey, where are you? Come kiss me again. She loved being held. She loved her friends and she was tough. She was strong. She faced a lot of challenges that I’ll talk about more in a second, and really was up to them. We would play or do physical therapy and she tried so hard to lift her head up to stand with support, to sit to look at different things, all of these things that we take for granted, but that were for her really, really hard. And she was just an amazing person. And I miss her and I’m really grateful for her, what she is and what she was in my life and my wife June’s life. As far as her diagnosis and our journey to get there and what we were told when she was diagnosed—I said we came home from the hospital and everything was normal, [but] around six weeks after she was born, June and I started to become concerned. She wasn’t smiling. And usually, you smile between four to eight weeks or so. And we started talking to our first primary care physician at that time around our concern. And I think a lot of parents in our disease community and others, initially the primary care physician wasn’t really interested, didn’t share our level of concern, probably thought just a couple of overly concerned new parents. But I think beyond the smile, June and I each developed independently concerns about, “Hey, yeah, she seems different and struggling a little.” The beginning of the diagnostic odyssey was just us sort of raising our hand or kicking and screaming and saying, “Hey, listen to us. We think there’s a problem here and we need to do something about it.” And I remember our physician at the time saying something like, I’m 90 percent not worried. And imagine to parents, 10 percent is a big number. And so, we really drove like, “Hey, can we see a neurologist? Can we see an ophthalmologist because of some eyesight issues?” And okay, fine, so that led us into the next phase of being followed by neurology and a brain MRI that showed up normal and some genetic testing, not sequencing, but microarray testing that came back normal. And we had between two months and eight months, her slide really starting. And she was having problems with tummy time and normal developmental stuff and started to develop feeding issues and us not being able to do anything about it because we didn’t know what was wrong. And when she was about six months old, we asked, can we see a gastrointestinal doctor, a GI? And I didn’t even know what that was, but my dad said, “Hey, you guys should see a GI.” And so, we asked our primary care physician who said, “sure, why not?” And we got a swallow study scheduled. It took three weeks to get a swallow study scheduled. We just couldn’t get on the calendar. I think I called three times to get it rescheduled and pulled forward. And she failed that swallow study and what we thought was an in and out checkup. So it became a three week hospitalization and surgery to have a feeding tube and some scary stuff while we were in the hospital that unlocked the availability of exome sequencing for us. And insurance wouldn’t pay for it before then and this was seven years ago. So, I hope and believe that exome sequencing is more accessible now to people like Yaya and families like ours. When that exome sequencing came back, her genetic differences were identified. And I’ll never forget the day we met with our geneticist and told us Yaya was affected by 4H. He gave us two scientific journal articles that we had to try to read on what was then the hardest day of our lives and kind of figure it out. But at that time, he didn’t really tell us what to expect. I mean, we were in that appointment [and] I remember talking about what we should do once she reaches the age of puberty and we need to think about initiating puberty via medication and sort of a long time horizon. And when we read those journal articles again and again and again trying to learn about the condition, what we saw was the cases in the journal articles presented later, like 18 to 24 months. Yaya was presenting at six weeks or even before then and it didn’t make sense to us. We ultimately connected with the person who wrote the article that we were reading. We found her and saw her, and she helped us make sense of the condition and helped us refine our expectations—that Yaya’s case was really severe that we should start thinking about things like palliative care. And that really helped us, that diagnosis and being able to refine it and understand what Yaya’s case looked like, helped us make sense of it and make good decisions for her, good care decisions that I think made the most of her life and our life together.

Daniel Levine: How did you go from the experience with her diagnosis and her death to create the Yaya Foundation?

Ron Garber: Yaya died. When Yaya died, there was a huge hole, sorry, give me just a sec here. When Yaya died, there was a huge hole in our lives. Literally there was a huge hole. We spent so much of our time and energy and care and love just taking care of her. By the time she died, her care had just become really involved and we spent so much time every day making food for the feeding tube and physical therapy and music therapy and just all these things. So, there was a huge hole, but really spiritually, there was a big hole too. We wanted to continue to be her parents. We wanted to continue to give her life meaning. And most of all, we didn’t want to accept that this was a thing that could happen to kids like Yaya and to other parents. But before Yaya was diagnosed, neither Jean nor I knew anything about rare disease, probably didn’t even know that rare disease was like a thing—sort of a category in the healthcare world. And we had always thought that you figure out what the condition is and then there’s a medicine or something you can do about it, and maybe that’s overly simplistic, but we certainly thought that when we got to a diagnosis, there’d be something we could do to help her. And certainly, that we’d understand what the condition was and what to expect and what we could do to mitigate the effects. That wasn’t the case for us. And we wanted to change that for other people like Yaya, and other parents like us. So, for a year or two, we were struggling to just move forward with our lives in general and grieving Yaya, but thinking about what can we do. What can we do to help other people like her? And ultimately, we learned of a matching grant opportunity just for any nonprofit contribution. And we thought, oh, this is the sort of trigger, what we need. And I think it had a one month sunset on it. So that was really the catalyst for us to say, “Hey, let’s raise a little money. We’ll get this match and we can leverage that to start bringing other people in and start talking to scientists.” So, we did that. We found a friend to help us get 501c3 tax status, and we learned about that as we did it, sent it into the IRS, and got tax status back. And we also, in parallel, reached out to two other families that we had found online that were doing a little bit of fundraising themselves, a family that was running a golf tournament and a family that had done a dinner fundraiser and said, “Hey, we’ve raised a little bit of money. I think if we put our heads together, the sum will be greater than the whole of its parts, and maybe we can attract the attention of some larger funding sources and get some stuff done together.” And they were in and we were kind of off to the races after that.

Daniel Levine: The foundation’s mission in part is to accelerate and support research that will lead to the development of a therapy and cure for patients. As part of this, you established the 4H Leukodystrophy Collaboration Network. What was the vision for that?

Ron Garber: Yeah, so when we started, we had no idea what to do. And another parent who had done some similar work who we were introduced to said, “Hey, why don’t you just send out a request for proposal to a couple of labs and you can see what comes back and you can fund something, you can fund the work that you like.” And so that said, “Hey, let’s do that.” And so, we sent out an RFP to the three academic labs that we knew were doing work in 4H in Montreal and Amsterdam and in Philadelphia. And two of those labs sent proposals back. And those proposals were really confusing to us. Basically one assumed answers to the questions that the second was trying to answer. And so we were like, wait a second. Do we need to know the answers to the questions in the second proposal before we fund the first? Or does someone already know the answers to the questions in the second proposal and we should just fund the first and not waste time? So we had no idea what to do, which proposal to fund, and we started calling people. And that’s when I got in touch with a rare disease venture capitalist named Walt at Third Rock Ventures, who I had spoken to when Yaya was alive and when I was trying to find something, anything that would help her, and I asked him what should we do here? And he said, you guys need a strategy. You shouldn’t just be funding one-off proposals. You need a strategy and you should talk to I think he said 30 people, you should talk to 30 people and you should come up with a strategy regarding how you’re going to attack this. And so, we did. By that time, I had gotten together a board of directors for the YaYa Foundation, and we started talking to other patient leaders, other parents, venture capitalists, some pharma, biotech, drug developers. And we learned of work that the Castleman Disease Collaborative Network was doing around collaborative research networks and were really inspired by that because it was a strategic approach to leveraging unique contributions that patient communities can make to bring researchers together and get them working together and to find the right work to support—to do together—with the limited resources that we have, and then to work together to get it done and share data. So, we started doing that. We will talk about CZI in a second, so I don’t want to get ahead of ourselves, but we started talking to all the researchers we could find on PubMed and had conversations with them over a summer and basically found out all the work that everyone was doing and wanted to do and called a meeting, got everyone together and over two days, discussed all of it together. And coming out of that, we were able to come up with a research strategy as a patient community that we’re still working today to advance and support and achieve.

Daniel Levine: Walk me through that. How did you go about setting a research agenda as someone who didn’t know what a rare disease was just months before?

Ron Garber: Yeah, so a huge catalyst of our work was the Chan Zuckerberg Initiative “Rare as One” program. And just as we were thinking, just as we learned about the Castleman Disease Collaborative Network and that’s what we should do, that’s much more effective as an approach than just the fun one-off stuff. And we started, basically it was me and our board, in June started identifying people and trying to set up calls with people and plan an agenda for a meeting. And when we were really deep into that work stream and then CZI put this request for application out for patient organizations just like ours that were trying to start a collaborative research network. And we submitted an application and were selected as a cycle one grantee, and that gave us some resources. And so, the first thing we did was engage a geneticist who’s our science and research director to this day, Valerie, to work with me—who knows nothing about me, who knows nothing about science or research or drug development—to talk to everyone that was doing work and do what I was talking about just a second ago, and identify the skillsets that were not represented among that group of people to invite, to connect with that group of people who knew the disease to crowdsource ideas. So, Valerie and I spent the summer talking to people. We had that meeting in parallel. We set up an informal scientific advisory board, and Walt was on that together with a clinician researcher and another biotech venture capitalist, Tom, and they sat in on the meeting with us and we set up the meeting. So, disease experts spent the first portion of the meeting talking about the disease. Then everyone that was doing work in the disease talked about the work that they were doing, and then a few key therapeutic experts in a few key therapeutic modalities that we thought could be helpful in our disease—cell therapy, gene therapy, small molecule—talked about work they were doing. And then we spent some time just debating what’s all the stuff we would do if we had the resources, and parents and patients were there too. And coming out of the meeting, the scientific advisory board, the Yaya foundation team, and a couple of parents worked through the output of that meeting together and kind of messily put together different buckets of work to advance, like okay, natural history data is a key need for our organization. Gene therapy, cell therapy, small molecules are all therapeutic modalities that are interesting, and gene therapy seems to be the furthest along, and have the specific projects identified that can move the ball forward. Tool development was another one. We need tools and models that would support discovery. So, we kind of came out of that meeting with some sort of like swim lanes that we wanted to advance was some projects in the swim lanes and we had a finite number of resources and just debated as a group where to put those resources towards projects that we identified in that strategy.

Daniel Levine: You mentioned CZI. This is the Chan Zuckerberg Initiative’s “Rare is One” program you’re referring to. This has provided not only funding but also really giving you guidance and help shaped what you’re doing. What would you say you’ve been able to get from that program?

Ron Garber: So pre CZI, the Yaya Foundation was mostly me late at night after a long day of work and putting our two living children to bed and sending out emails to researchers and trying to move the ball forward. CZI brought funding to help build out that team to support that work so that we could have people working during the daytime too and expertise that I didn’t bring. But more than that, it brought capacity building and networking to the work we were doing. So we were part of a network of 30 other awesome or 29 other awesome patient organizations. We learned from what they were doing that informed our research strategy and it informed how do we conduct the scientific meeting that I talked about where we tried to set that research agenda. And we have 29 other patient organizations to kick ideas off of, and experts from the outside, like Chordoma Foundation who had just done a scientific meeting just like the one we were trying to do. And Josh, who leads that organization, came and presented to our group and we could ask them questions and learn from the work he had already done and not have to reinvent the wheel. It gave us nuts and bolts resources. So sure, we all need to be experts in data collection and drug discovery and so forth, but we also need to know how to run a business, a nonprofit business, but still a business. We need to learn how to raise money and have a stakeholder management system and a board of directors and all this sort of blocking and tackling and less exciting stuff, but fundamental stuff that comes with running a patient advocacy organization. Andra Stratton, huge shout out. Andra leads capacity building for the Rare as One network and just connected us with so many resources and so much learning that helped us do that more effectively. And so between some funding and a team and all those resources, it just upped our organizational capacity so much and I’m so grateful. And now a year later, we’re a year out of the program and we’re still just, I think, operating at such a high level. So, it’s really validation for what that network was designed to accomplish that we came out of that three-year cycle operating at such a higher level than we went into it.

Daniel Levine: The Yaya Foundation was also an early participant in the RARE-X data platform. How did the organization come to recognize the importance of gathering patient data and the ability of patients to control access to their own data?

Ron Garber: So, coming out of that scientific meeting, I mentioned one of the needs that we identified was natural history data and a common way and a good way, frankly, a way that we’re still focused on of collecting natural history data is working with an academic institution to conduct a natural history study in which typically an academic lab will follow patients and gather data and hold onto that data. That’s expensive. It ends up often with data being siloed in a particular institution and not being accessible broadly across a big community of people around the world who can help. And it often leads to patients giving away data and not controlling who has access to it beyond that lab. And by the way, all that is important. And like I said, we’re working with three institutions now to advance a natural history study just like that. It’s important, but it’s probably not enough. And so, what we loved about RARE-X was it’s a low cost, or for us at the time, a no cost way for us to gather critical data. We don’t have to become data collection experts ourselves. Data collection is very complicated and we’re trying to do lots of things. And there are 7,000 plus rare diseases and hopefully 7,000 plus rare disease organizations. And it is inefficient for our broader rare disease community for each of us to have to develop deep data collection expertise on our own. And so we just felt like we found an expert, we found someone who could help us achieve our goals really efficiently. And then the cherry on top was our patients control who that data is shared with, they control if it’s even shared with us as a patient organization, but they have the option. We have the option to share that data with scientists, researchers, drug developers, all over the world beyond just our 4H community as it exists today. And that was really appealing to us because our patient community wanted that data to be available to anyone that could help us. And so, coming out of that meeting, that was one of the bets we made—putting resources behind working with RARE-X to launch a RARE-X data collection program.

Daniel Levine: One of the things you also have been able to do is connect with Genevieve Bernard at the Research Institute of the McGill University Health Center. How did you make that connection and build that relationship?

Ron Garber: Yeah, so when Yaya was diagnosed, I mentioned that we got those journal articles. Genevieve had written one of them. And so, when Yaya was diagnosed, one of the first things I did was call a friend of mine who had been just a support through Yaya’s life to that point and who was a doctor and was helping us get smart and make decisions. And we sent the journal articles to him, and I think he had Skyped with Genevieve by the next morning. He’s that kind of friend and she cares that much about our patient community. So, she was the person that we went to see about a week or so after Yaya was diagnosed and she shared really hard news with us, but in a very kind and caring and compassionate and constructive way that, like I said, helped us make good decisions for Yaya. So, that’s how we initially connected with her and we stayed in touch with her as we launched the Yaya Foundation. And she also helped us connect with other researchers and clinicians and scientists that she was working with or that she wanted to work with or bring into our community. And she’s been, she and Nicole Wolf in Amsterdam, and Aline Vanderver and Laura DeValdenebro at CHOP, and Ian Willis in New York, and Florian Eichler at Harvard, have been great partners for us as we try to build out our research community and move the ball forward.

Daniel Levine: Bernard’s lab at McGill recently achieved a milestone by creating the first animal model for 4H leukodystrophy. What’s the significance of this? Why does it matter?

Ron Garber: Yeah, it matters because it gives us a couple of things. One, we can study. A disease model is so important. We can study it to learn about the disease. We don’t know very much at all about why 4H shows up the way it does. Why is there abnormal tooth development, for example, what is happening? What is the pathway that’s leading to that symptom? An animal model allows us to study the disease and learn about the pathophysiology and identify targets for therapeutics. If we know more about what the disease does, we can target it with some drugs. And then it also gives us a tool to develop and test therapies. And so that mouse was completed, it’s being published now, in brain. It was completed a little while ago, and already since the completion of that mouse, we’re working on testing a gene therapy treatment by delivering a gene therapy to the affected mice and trying to refine that therapy to see if it changes outcomes for the mice. And so, we can do that not only with gene therapy but with small molecules, maybe with ASOs. And so, it’s a really important tool that we think will move the ball forward really meaningfully in our quest to find a treatment and ultimately a cure for 4H.

Daniel Levine: As other patient organizations might want to take similar steps to advanced research, can you give a sense of what it took to get to this point? How much time, money, effort went into developing an animal model and what did that involve?

Ron Garber: Yeah, it took a lot of time and more money than we wish for sure. And I want to make sure I answer this question in a way that isn’t scary or that doesn’t feel prohibitive for someone in the position we were in seven years ago. First of all, I’ll just say in our case, it’s a really complicated mouse because there had been previous attempts to try to develop a mouse model for 4H, and with the severe mutation, the model didn’t live. And with a normal mutation, it didn’t present because mice have less myelin than people. So it was hard to develop a good model. And this model is more complicated than the usual mouse model. And so it was expensive and a couple footfalls went into it before a successful attempt. And the reality is putting together a collaborative research network and having all those calls to survey the landscape and bringing in partners to assess the information and make good decisions about what works to prioritize is time consuming. And it’s taken, frankly, the mouse gene therapy project, the first phase of that was a $400,000 project. That’s not small money for our small patient communities. And that’s one case. There are many things that we as patients and parents and advocates can do. And my answer to this question is just do something. We can all do something. We don’t have to raise a million or $2 million. The road to a cure is like a puzzle, I think. And we all, as patient communities, can identify some puzzle pieces that fill out that puzzle. And even if we had just sent out that RFP and funded one of the proposals and done some kind of small scale fundraising coming out of that, that would’ve been great. It would’ve moved the ball forward for people in our disease community with a serious need. And so in our case, it took a lot of time and not a small amount of money and certainly a lot of effort from our team, and it’s just one way to do it. But it’s been, I will say that it is been really fulfilling and it’s been a really good use of time and money and effort, and it’s going to help people, enriched my life and the lives of the people who’ve been a part of the effort, and it’s just one way to approach it.

Daniel Levine: You mentioned you’re doing work on a gene therapy now. Who’s involved in that work and where are you in that process?

Ron Garber: Yeah, so one of the things we as patients can do is just bring people together, even if we’re not bringing tons of effort or time or money. And this question is a great example of that. Genevieve knows the disease really well and had done some work with others on model development, like I said, and also is a great collaborator and good at identifying where there are needs for skillsets to be added and then working to bring people in. And we, in that scientific meeting, invited Guangping Gao, who’s the president of the American Society of Gene and Cell Therapy and works at the University of Massachusetts, to partner with her on the next phase of that gene therapy project. And so, they’re now working together and they’ve developed a capsid and even are starting to deliver gene therapy to the model. I think it’s hard to say no. They wanted to say yes, they wanted to work together, but I think it’s really hard to say no to a patient or a parent. And so, one of the things we can do is if there’s a skillset missing or a gap, I think we can work together with who’s already at the table to identify the right person or people to invite into the team. And I think it is really hard for people to say no to people like us, and that’s great. We can then sort of fill out the puzzle. And we were able to do that together with Genevieve and Guangping and their teams to sort of couple a disease expert with a gene therapy expert. And that’s already moving forward, and we hope that partnership will be really fruitful.

Daniel Levine: I know people who’ve experienced the type of loss you have could just be paralyzed by it. And it’s amazing to see not only how much you’ve accomplished since then for others, but also the speed at which you’ve been able to do that. You’ve managed to come a long way since the foundation was started just five years ago. What advice would you offer younger patient organizations on what they can do to accelerate progress to treatments and even cures?

Ron Garber: Well, Danny, first I appreciate that question because it doesn’t feel like a short time. It feels like a long time, five years. And so I appreciate your encouragement that it looks like we’ve come a long way in a short period of time. So thank you. Look paralysis and not knowing what to do are appropriate states of emotion. I think for people who are grieving a diagnosis or a loss, the first thing to recognize is that it’s okay to feel that way and to not know what to do and to not feel like you have the strength to do anything to help. And that’s certainly how I felt seven years ago when Yaya died. And so my advice is just do something. In my case, I asked some friends who I thought could help to, “Hey, help me out. I just want to explore this. Will you sort of kick ideas around with me and just help me out?” I didn’t say it, but I probably also meant give me encouragement. Tell me I’m doing a good job, support me emotionally at a hard time. And they did. So that was an important step for me. And beyond that, it’s just do something. We’re all good at something. There are amazing parents and patient advocates who become scientific experts or PhDs. That’s not me. But I think I’ve been good at just effort and resilience and bringing people together. Some people are good at raising money. Some people are good at organizing a 5K event or a golf tournament or cold calling researchers. We all have something we can do. And my advice is just take the first step. For me, that first step turned into the RFP, which turned into this problem of which proposal we fund, which turned into the conversation with Walt about you need a strategy. And I think during all of those steps, I sort of gathered energy and felt an increased sense of purpose and meaning in my life and free Yaya’s life. And that energized me and gave me an outlet for the grief I was feeling at the time and turned into this really big effort. I think five years ago, I would not have guessed. I was just having a conversation with one of those friends and I said, I don’t think any of us ever expected us to be where we are now five years ago. And he was like, “what are you talking about, I did.” But I don’t think I did. I don’t think I did. And I think just doing something when you feel paralyzed, call a friend who’s a lawyer to help you get 501c3 status, or talk to another patient organization that’s in a similar spot to see if you can work together or learn from them. Just taking the first step. You never know where it’s going to lead, but it’ll lead someplace good.

Daniel Levine: Ron Garber, co-founder and board president of the YaYa Foundation. Ron, thanks as always.

Ron Garber: Thank you, Dan.


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