From Mila to Millions: Scaling N of 1 Therapies  

When Julia Vitarello learned that her daughter Mila had the CLN7 form of the deadly, neurodegenerative condition Batten disease, it set her off on a search for a treatment that resulted in the development of a customized antisense oligonucleotide. In the wake of Mila’s case, a movement has emerged to develop so-called N-of-1 therapies for people with ultra-rare conditions. Vitarello, along with Boston Children’s Hospital researcher Timothy Yu, who developed the ASO to treat Mila, has co-founded the N=1 Collaborative, an international group seeking to enable the development of N-of-1 therapies to treat the thousands of patients in need. We spoke to Vitarello, CEO of Mila’s Miracle Foundation and co-founder of the N=1 Collaborative, about the new organization, the issues it is trying to address, and what it would take to take enable the development of individualized therapies broadly for patients with ultra-rare disease.

Daniel Levine: Julia. Thanks for joining us.

Julia Vitarello: Thank you, Danny. Thanks for having me.

Daniel Levine: We’re going to discuss the N=1 Collaborative, the work it’s doing through its international network to address challenges of delivering individualized antisense, oligonucleotides to patients in need. I’d like to start with your own story, which led to its creation. I suspect many of our listeners will have some familiarity with your daughter, Mila, who had the CLCLN7 form of the rare neurodegenerative condition, Batten disease. What was Mila like?

Julia Vitarello: Mila was born completely healthy. She was really outgoing. We live in Colorado and so she was a skier and a rock climber. By the time she was two years old, she was like any other kid. She was swimming and singing songs and playing with all her friends and everything seemed completely normal. She was my first child, so I didn’t have anything to compare it to, but she was extremely outgoing and very verbal and very coordinated. And everything seemed to be fine for the first few years of her life.

Daniel Levine: When did you first discover a problem and how did her condition progress?

Julia Vitarello: Around three and a half years old, because we hiked a lot and we would hike on end, I started noticing that her feet were in-turned, but the orthopedic doctor said, “oh yeah, that happens, that’s tibial torsion or something and kids outgrow that and a percentage of kids have that.” But then with time, I think around four years old, she started kind of stuttering, but it didn’t sound like typical stuttering. I brought her to a stuttering therapist, and she was a little confused because Mila would start to say the first few words of a sentence and then stop and kind of get stuck on that word, which often became mommy, so she would repeat mommy over and over again. It really drove me crazy and I didn’t understand what was going on. Then with time, she started sticking her face up really close to her toys. She would be putting little figurines on a little tiny house and she would get really close to them. So, I brought her to the ophthalmologist and the optometrist, and they all said, “well, you know, looks like things are okay. We’ll just keep an eye on her over time.” And each of the different doctors or therapists explained that she would grow out of whatever symptoms she had, but I had a little piece of paper that I started. It was a little scrap piece of paper. And I wrote, neurological symptoms? And to be honest, I barely knew what a neurological symptom was at that time. But it seemed that there were too many things that were going on over time and I wondered if they were related to her brain. I would bring them to each appointment and honestly, none of these doctors could see past their own very specific area. They couldn’t look at the fact that it was not just a vision problem and it was not just an orthopedic problem, not just a speech problem. In hindsight, I certainly wish they had realized that if you have more than one potentially neurological symptom, you should probably dive into it a little bit more.

Daniel Levine: How old was Mila when you got a diagnosis and what were you told about the condition?

Julia Vitarello: She had just turned six years old. I remember going on a run right around her sixth birthday, and I was just crying the entire run. I could barely breathe because I was sobbing so hard and that was a sign to me that I don’t usually cry like that and certainly not when I’m running. It just was a sign to me that something was obviously much more serious than what people were making it out to be. And I really couldn’t take it anymore because I had dragged her to, I think I counted at some point like a hundred different doctor and therapy appointments over the course of two and a half years. I literally couldn’t do it anymore and I had an infant son, and I was alone dragging these two around sometimes on airplanes to various places in the country and with no answers. I brought her into the ER of Children’s Hospital Colorado, which is the closest hospital to us. They were on high alert because they turned the lights off and put a flashlight in her eyes and she didn’t respond to it. And then they said, “oh, I think she had a seizure.” And I had no idea she had a seizure. I had never seen anything. I barely knew what a seizure was, which landed her in the hospital for a week of tests. And that ended up in kind of two possible diseases that they thought she might have, both of which were terrible. And then the genetic test came back. A lot has changed. That was in the end of 2016. So obviously, now you can just run a genetic test, but at the time there had to be this battery of other clinical tests before. After that, we got this diagnosis about a week later of Batten disease and I was very relieved at first, like a huge weight was lifted off my shoulder shoulders because I just thought that finally there was actually an answer and everyone had kind of made me feel like I was crazy, to be honest, and that Mila was just going to grow out of these symptoms. Then I started learning and reading about Batten disease and there was pretty much nothing worse that I could imagine—you know, reading that a disease was going to take my daughter’s vision completely and her words and her ability to eat and stand and walk and swallow. And eventually she was going to die in just a few years’ time. I mean, I just went in my closet every single day, 10 times a day and just cried as hard as I could and hoped that my kid couldn’t hear me.

Daniel Levine: Rarecast listeners may recall a past episode we did with Timothy Yu of Boston’s Children’s Hospital. Listeners can find that episode as number 301 in our archive. How did you connect with Tim and how did the potential for a customized antisense oligonucleotide come up about?

Julia Vitarello: Yeah. What happened was when Mila was diagnosed, Batten disease is autosomal recessive, which means she had to have received a mutation in the MFSD8 gene, which is associated with Batten CLN7. She had to receive one mutation from her mom and one from her dad. So, they could only find one and they reran these genetic tests a number of times in these clinical labs. And they could only find one. I was told by Neil’s geneticist correctly at the time that diving deeper would be hard to find the other mutation and that I should probably try to just accept this diagnosis because clinically she she fit the mold for the CLN7 Batten patient of six years old and the one mutation that had been seen before, they found, so it made total sense to him. And he was correct in saying that it would be very, very hard to find a lab that might be able to find the missing mutation and even if they did it might be in an area that might be really hard to even prove that it was disease causing. Despite giving me that difficult news, he also was very helpful in making sure that as I pried and said, I really want to know more, he tried his best to help me and put me in touch with some other labs and some people, but nothing happened. So, I finally went to Facebook and just said, look, I’ve done my homework here. It looks like whole genome sequencing, which once again, five years ago at the time was very unusual. And I said, it looks like from what I can understand, that’s what I need to do because it’s going to be my very best shot at finding this missing mutation and I need to be sure; I need to find this mutation because I need to be sure that Mila in fact has Batten CLN7 so I can work on a gene replacement therapy or something to go after it. And I needed to be sure she in fact had that disease. My son Alan was only two years old at the time and Mila had been perfectly normal at two. And so, I was terrified every day and every night I put him to bed in his crib. I would just be bawling because I just thought, now he’s going to lose his vision and his words, and he’s going to die too and I’m going to have motherhood taken from me. So, I needed to be able to test him and I couldn’t fully test him unless I had both mutations. So, I went on Facebook and made a plea, and I grew up on the east coast and I knew people that had gone to Harvard. So, I just said, Hey, Harvard has a lab where they do whole genome sequencing, but it takes five months and it’s $25,000. And I need help getting in really fast. I don’t have five months. And that landed—through my amazing best friend from Amherst College, Jess Flynn, who’s a doctor in Boston and she reposted it to a group in Facebook of female mom physicians. It was some closed Facebook group. And that ended up on Dr. Timothy Yu’s wife’s desk, which then that night got brought home to him. He looked at it and then sent me an email and said, “Hey, I saw your story. And I have a lab that looks for difficult to find mutations, and I’d love to try to help you out.”

Daniel Levine: How long did it take from the time the decision was made to develop an ASO for Mila to her first dose?

Julia Vitarello: In the first few months, right after meeting meeting Dr. Yu, which was, by the way, just a month after Mila was diagnosed, they spent the next few months saying, “Hey, keep working on your gene replacement therapy.” You know, I started Mila’s Miracle Foundation. I’d started working on gene replacement therapy because it was the only option. And during that time, Dr. Yu and his team started looking into an antisense oligonucleotide after figuring out what Mila’s missing mutation was. And when they found that missing mutation it ended up opening up something that they had never imagined, which was a possible therapeutic, which was not what they were looking for. They were just trying to help me find the missing mutation and that possible therapeutic was an antisense oligonucleotide, or an ASO, similar to Spinraza for another devastating disease in children called spinal muscular atrophy. That had been a very promising drug that had been approved by the FDA, the exact same month that Mila was diagnosed. So, it was on everyone’s mind and it was a game changer in neurology and meant that neurologists could actually potentially stop diseases and not just treat symptoms. Mila’s mutation looked like it was amenable to a similar type of ASO and that kind of came up in the spring of 2017, so a few months after I met Dr. Yu and when he brought that idea up that was something around April 2017, I believe. By January of 2018, we had moved to Boston and to speed up the enormous amount of work, which I’m sure Dr. Yu talked about in his podcast that went into making milasen happen. It turned out that they were able to design an ASO. They were able to test it on Mila’s cells and show in a number of different independent labs that it was restoring health to Mila’s cells and the lysosomal buildup was going away. On top of that, getting an FDA green light to move forward after manufacturing it and testing it in animals. It was done at breakneck speed in only seven or eight months, it went from an idea to an actual treatment that Mila was beginning to receive, and only one year from her diagnosis,

Daniel Levine: Mila died in February 2021. It was a loss felt throughout the rare disease community as many people closely followed her story. You mentioned some of the scientific results of using milasen and the benefits she got from it, but did you see visible changes? Was there evidence that it slowed the progression of the condition?

Julia Vitarello: Some things were very noticeable and other things were subtle. I didn’t know what to expect going into it. I just knew that there’d been 30 years of work and animal studies on ASOs and that the risk of treating Mila was that this was a new drug and that we didn’t know much about it, but that there was a lot known about ASOs and the risk of not treating Mila was very, very black and white. It was that she was going to lose all of her abilities and die very soon. And she had been spiraling down right before milasen. So, just about a month and a half before or two months before, she took this very sudden kind of cliff, typical maybe of a Batten disease where she started having visible siezures and they got more frequent and lasted longer and longer to the point where they were sometimes up to 30 a day and they were lasting two minutes each, and she was shaking and smashing her arms and legs on tables and was covered in bruises. And she had gotten a G tube because she could no longer be eating by mouth. She could eat a little bit period food, but it was becoming less and less to the point where leading up to meals and she barely was eating anything by mouth because she was choking on it. She had begun slumping over a lot which made it very hard for her to sit up, even propped up. It made her hard when I would hold her from behind, and she could no longer stand by herself. Taking steps was very hard for her because she was slumped over and most importantly when I would sing the same songs and read the same books at the exact spots that she thought were hilarious, because Mila was really just such—she laughed and smiled all the time, her whole life. And she was starting to do that a little less. Once we started milasen, within a few months her seizures were the most obvious thing. That’s what Dr. Yu, obviously, ended up publishing on in the New England Journal of Medicine. That was very black and white in the sense that they got much less frequent throughout the day. And then they got much less severe. They lasted a shorter time to the point where as I was monitoring them religiously every day and keeping track of them in a file they got down to the point where there were days she didn’t have any at all. And even when she did have some, if you walked into my home, you would not even notice that she had any seizures. She was barely—maybe move her head, a tiny, tiny bit for a few seconds, a few times a day, so that was drastic, and it really allowed for a really big improvement in quality of life. Not having seizures means that you can actually go out of the house and you can sit at a table and not be covered in bruises. And we cannot be scared of choking on something exactly in that moment when you feed her that she’s having a seizure. So, that really helped, but other things were that she sat up a lot. She held her body and her head up stronger and straighter, which means she could sit unattended, which she hadn’t done before. For a while, it meant that she could—she started lifting her feet, so stronger legs too. She could lift her feet and hold her body up with me holding her from behind. And she could go up the stairs. It wasn’t all the time and every day, but it happened a number of times and that she could go all the way to the top of the stairs, alternating her feet, and other times it was just halfway. Those are, you know, movement is important. She felt like she could move around, and I would hold her from behind and she would take steps around the house. And then she started eating by mouth, which was huge. She ended up doing that for a number of years and she ate pureed food by mouth, and she was able to enjoy the taste of food and not have it go through a G tube in her stomach, once again, really helping her quality of life. And most importantly for me was that when I would read the books and sing the songs, it was not perfect. She didn’t laugh and smile every single time, but it was certainly an increase, and she really was just more alert and responsive to things. And that was hugely important to me.

Daniel Levine: What is it about antisense oligonucleotides that make them well suited for this type of customized approach to treat people who have an ultra-rare genetic disease?

Julia Vitarello: My preface here is that I’m not a doctor or scientist, but I have been around this obviously the last five years, so I can give you a non-scientific reason why. In the past we have treated diseases and conditions and genes—so larger groups of people. Now that we know in many cases what the underlying mutation is, what Milo’s story has shown is that you can target or customize a drug, in this case an ASO, for the actual underlying mutation—in her case no one else in the world had her mutation besides me and my mother who passed it down to me. But there was no other child with Batten disease that had the same mutation. So, it ended up being that this drug targeted her very specific mutation, and she was the only person in the world who could benefit from that, hence why it was called milasen. It was named after her because only she could benefit from it. ASOs are designed around a very specific, and in her type of ASO, a splice modulating ASO, is looking very specifically at the mutation causing her disease and it was kind of cloaking it or covering it up. So, my way of describing it is that by cloaking it, it allowed the coding region of her bad gene to read correctly and actually produce that protein, whereas before it couldn’t because of this mutation. So, it cloaked it, which allowed for that to happen. So, why it is well suited is because it’s a programmable type of modality. It allows for another child to have an ASO made for their very specific mutation, which is different than milasen. But the entire process, A to Z of designing and testing and bringing that ASO to the child is exactly the same, and even how you manufacture it and everything about it, how you administer it. The only thing that’s different is that the actual design of the ASO for Mila would be different than the design of the ASO—the sequence of letters—for a different child. You can kind of program them and swap them out, but the rest remains the same. So that’s one of the reasons ASOs are particularly interesting when it comes to an individualized approach.

Daniel Levine: Early on you and Tim discuss creating an organization that would help others do what you did. You helped found the N=1 Collaborative. We’ve seen both nonprofits and for-profit efforts emerge to create ASOs for ultra-rare conditions. What is the N=1 Collaborative and what is it seeking to do?

Julia Vitarello: Tim and I, I would say within year after Mila was treated, I think it really hit both of us that we had been just trying to find a treatment for Mila to help her, but it was never that we were looking for an N-of-one that didn’t even exist before. We realized that Mila had been the first person in the world to receive an entirely new or novel genetic treatment that was targeted to one individual person. And that’s what caught the attention of the entire scientific and medical community and started realizing that this could be applicable across many diseases. And that was something different, you know, because in rare disease where—look, I’m a rare disease mother—we’re desperate to have treatments. I know that going gene by gene with 7,000 or more rare diseases is going to take thousands of years possibly. So, having this programmable ASO approach to rare disease started seeming like a really interesting and promising way, a very different way, of approaching treating patients with rare disease. In one of our presentations that Tim and I gave, and we gave many of together, and we still do where he gives the scientific part and I give a little bit more of the part of having lived this experience, we had a slide. I remember in one of our presentations that Dr. Yu put together where it showed Boston Children’s and then it showed Colorado Children’s because we were trying to move Mila’s treatment, which we ended up doing closer to home, which made life a lot easier for us. After a few years, we did that. And then it showed maybe Stanford or another academic medical center and in the middle, there was a circle that said, N-of-one hub, and there was a slide to say, well, what if we continued having more and more academic medical centers like Boston Children’s and more PIs like Tim do this, and what if this starts to grow and become something that cuts across many rare diseases, and that slide ended up being what kicked off the idea, and many, many conversations with academic institutions around the world including the Oligonucleotide Therapeutic Society, which is an academic society that works on ASOs. Working with them, we decided and eventually, this was in the summer of last year in 2021, launched the N=1 Collaborative. When we launched it, the purpose of it was very specifically to see how do we make what we did for Mila something that can be applied across many rare diseases? How do we make individualized medicines safely, which is really important, but really rapidly accessible to patients worldwide. What we envisioned was these individualized medicine centers in academic medical centers, maybe around the world, where patients like Mila could come in and our dream is that within six months, come back and there would be, it would be routine, you know—in six months and in $600,000, I’m just kind of making this up—and covered by insurance. A patient could come back and receive a customized treatment that’s targeting their condition’s underlying genetic cause, and really make this routine and not a one-off.

Daniel Levine: Who’s involved in the collaborative and how is it funded?

Julia Vitarello: The N=1 Collaborative is a group of really amazing, basically volunteers right now. It’s primarily volunteer, Dr. Yu and myself. There’s a lot of his academic colleagues from many different institutions, honestly, from all over the world—people that have followed Mila’s story who really would like to do what Tim has done, and they’d like to learn more. So, it came together as people volunteered and in kind of a scrappy way just like coming together and being like, all right, let’s start some workshops. Let’s start to talk about what are all the different pieces that are needed from starting to identify patients all the way through the trial itself. And let’s start breaking these into pieces and working through them and putting them down on paper, and basically collecting people around the world who are high level relatively hand-selected neurologists and geneticists who really are interested in doing what Tim did for Mila and getting them all together in one place and one hub around individualized medicine, starting with ASOs.

Daniel Levine: You sketched out a type of vision for how this ultimately may work. A lot has happened since the work on milasen, but where are the bottlenecks that exist today that need to be addressed, particularly given that in most cases we’re talking about progressive and deadly conditions where time is critical?

Julia Vitarello: Mila was treated. Since then, there’s been a handful, not even, of children with very devastating diseases that have been treated with an N-of-one novel ASO. But when I think about this, I look at the statistics—Global Genes has done a great job with this—and you see 400 million people worldwide with rare diseases. Half of those are children, 200 million. And then of those, you have 60 million who are children that are going to die before the age of five. And, you know, I spent my twenties in Italy. I lived there and the population of Italy today is 60 million. So, when I think about the entire country of Italy, every single person, being a child with a rare disease that’s going to die before the age of five, it seems so overwhelming. It keeps me up at night, and I think this is like a global health crisis. Now, 80 percent of those are genetic diseases. So, it may not be 80 percent, I’m sorry. It may not be that the entire 60 million are children that are dying before the age of five with genetic disease, but it’s still somewhere around 60 or 50 or 40—it doesn’t really quite matter what that number is, it’s tens of millions worldwide. And the way I look at this is that there’s an estimated maybe 10 percent, scientist researchers believe, of mutations that could be amenable to an ASO like milasen. And if you want to be really conservative and let’s say only 1 percent of those patients could be amenable to an individualized ASO like milasen, 1% of that 60 million or 50 million or 40 million—we’re still talking about hundreds of thousands of dying children who could benefit from a drug like milasen. And that does not include children who die later, after five years old, like Mila; that doesn’t include a lifelong debilitating disease. It doesn’t include adults. It doesn’t include any other form of ASO of which there are other types of ASOs such as allele or gene knock down, which is a different type. And it doesn’t include other modalities like CRISPR that are really following right behind us and could certainly be programmable as well. So, what does that mean? It means that to me, there are millions of people with rare diseases who could benefit from an individualized medicine approach. So, the question I land on and the one that keeps me up at night is how do we get from Mila to millions? And that brings me to your question about the bottlenecks and, you know, one of the big bottlenecks is our current regulatory path, and it’s no one’s fault, it’s simply that it was never designed for this new paradigm. It’s designed for a drug targeting a condition or a disease. It might be one drug for tens or hundreds of thousands of people or more. And now, if you think of this new paradigm, what if we had tens of thousands of drugs, each targeting one or a handful or two handfuls of people—that is drastically different and in order to face that it means that we need to, and I’d like to believe that we can, modernize the existing regulatory path. I will say that it’s very hard for me to imagine doing that because this is so different from what we’re used to and the risk benefit analysis, which is the base of the house where we kind of pour this cement that we’re going to build this individualized medicine house on top of, is very different than the risk benefit analysis for a drug that’s going to sit on a shelf for tens or hundreds of thousands of people. So, I’d like to believe we can modernize the FDA and EMA and other parts of the world regulatory paths, because it’ll be a lot easier than having to come up with an entirely new path. But it’s going to require really getting creative and thinking of what is correct and what is appropriate for this new paradigm. What is proportionate to the fact that these drugs are made for only Mila, or it doesn’t really matter me whether it’s one or six or 12 or 15, it’s extremely very, very, very small groups of people. And the repercussions of that drug are very limited and therefore have to be thought about differently. So, I think that honestly, the regulatory path, or to say it in a broader way, the technology and the science is there, and we have more and more and more patients being diagnosed with rare disease, and it’s getting access to that, which currently looks like the regulatory path. That’s the biggest the bottleneck right now.

Daniel Levine: You talk about from Mila to millions. Let’s talk about scaling in a little bit more detail and I want to ask you not only about regulatory, but also about financial issues and about manufacturing, and maybe we can take each of those separately. On the financial front, how do we take cost out of this process? And what would it take to get payers to recognize these therapies and provide reimbursement?

Julia Vitarello: Yeah, this is really good framing. I appreciate you bringing it up like this, because it’s true—how we get from Mila to millions is broken down into a few different areas. One of them is there needs to be good science and that’s the N-of-one collaborative, which we’ve just spoken about. We have to have a place where we kind of challenge and establish each step along the way, which I’ve just mentioned, and we need full transparency of data. So, like the good data, the bad data we need to make sure that’s fully transparent. That starts with Mila’s data, which I have volunteered and that’s going to be dumped into a database followed by everyone else who hopefully receives an N-of-one treatment. Otherwise, we’re in trouble because that data is very, very valuable. And we have got to make sure it’s transparent and we need more Tim Yu’s. And that’s the purpose as well of N-of-one collaboratives to grow more Tim Yu’s so more people could do this work. So, the good science is fundamental, hence, why the N-of-one collaborative is the first thing that we did. The second thing, and I agree with you, is we need to have a viable business model with reimbursement that has to be possible. And some people talk about this in a way like, well, you know, it cost about $2 million to do to, milasen. Not for us, it cost us less, but a lot of favors were called in since that was the first time this had been done, but let’s call it $2 million. Can the economy bear that $2 million? I personally think that’s a really bad way of thinking about this because when we’re talking about potentially trying to come up with a system where we have hundreds or thousands or tens of thousands of drugs, each for one or two or six people—it’s not appropriate. Why? Because the manufacturing cost for something like milasen at the time was somewhere between $50 and $200,000 for a lifetime supply of ASO. Now those prices have gone up significantly since then. They’re still in the hundreds of thousands, but that is extremely low for a lifetime supply of a drug that could be for a dying child, let alone for anyone, it’s very low. Obviously, the cost of milasen is not just manufacturing. Toxicity and safety are a big part of it and they are massive right now. They’re enormous, and in fact, they’re completely disproportionate to the fact that only one person is receiving this drug. So, one of the big ways to get the cost down is to think of a more appropriate and proportionate tox package and basically all of the requirements that are needed from the FDA have got to be rethought and be proportionate to this new paradigm so that we do not have to, you know, what I say is we climbed Everest, Mount Everest to make milasen happen. And some others can do that as well, but how many people can climb Everest? Not that many and it’s got to be that mountain has to be significantly lower. It has to be small enough that anyone who could benefit from an individualized ASO should have access to it right now. So, we need to drive down the requirements to be correct and proportionate—still safe, absolutely, but correctly proportionate, which is going to require a new mindset. I think that will then drive down the cost of the various pieces along the way, especially the toxicity and safety studies. Then as that becomes significant smaller, instead of being $2 million, if it’s $600,000 and I’m making that number up now, you know, it’s obvious that this is the future. The future is precision medicine, and of precision medicine the tip of that is this N-of-one or N-of-very, very, very small. And it’s where we’re headed and the insurance companies know that. So, I think if it becomes a little bit more manageable and there is a clear regulatory path, one other point that’s an important one is that this is reimbursable. Milasen fell in this no man’s land between research and compassionate use. And that didn’t really exist before, but it’s currently not reimbursable, and that needs to absolutely change because if it’s not, this is not about making money. You know, I lost my daughter to this. I’m involved in this for no other reason, except for that it’s unethical and incorrect that this technology exists and that children are dying in the tens of millions and that there’s no access between these two. And I want to make sure that there is a sustainable model and having academics spend two years, $2 million, and a thousand-page IND, with 30 people in their institution working on something for one individual child is not scalable and it’s not sustainable. So, we absolutely do need a viable business model with reimbursement, and I do think that will happen if we have a very appropriate and proportionate regulatory path, starting now. We need an on ramp to get from Mila to millions. We can’t wait any longer. It’s been four years.

Daniel Levine: The FDA has certainly been thinking about this and I get the sense they want to do right by patients, but is there some point where you think we could get to either a plug and play model where if you’re using the same vector, it’s just a matter of swapping out the oligonucleotide and that the FDA would allow that to go into a human being, or is it something that we might be able to develop a reliable either synthetic model or a model where this can be done rapidly to clear use in humans?

Julia Vitarello: Yeah, that’s a good question. I was very happy to see that the FDA issued four guidances around individualized ASOs over the course of 2021. That shows me, and I know this having spoken with the FDA many times over the last few years, that they’re very eager to do their very best to turn this into an accessible pathway. I think it shows that they care. I will say, however, that the content of those four draft guidances looked awfully similar to milasen and milasen was started four and a half years ago. There’s been two or three children who have received an individualized ASO since then, and that’s just not acceptable. It shows that Mount Everest is the same if not higher. So, in order to think about how to be able to make this more routine, we know that the process from A to Z is exactly the same, except for the ASO design itself, which makes it programmable. So, we still have to gather a lot of data. Only a few people have been treated with these individualized ASOs, and ideally the companies that have worked on larger ASO trials would be allowing for some transparency of their data, because that would certainly help. It might be idealistic to imagine them doing that, but it would certainly be helpful, and we need some sort of pilot that is the kind of on ramp from Mila to Millions, which allows Dr. Yu and many other scientists in the N-of-one collaborative who want to take on these treatments to be able to do it in a safe, but also proportionately an appropriate way to be able to treat more patients, because if there isn’t a pilot or if there isn’t a way to be able to do these more rapidly, then we are literally not going to treat any children, which is unethical, and we’re not going to have the opportunity to collect the data that we need to learn to be able to scale it. So, if Everest is this high, we’re going to have a handful of people able to climb it—and that’s it. Whereas if we come up with a more correct and appropriate and proportional kind of regulatory path right now that will allow Dr. Yu to be able to treat children, I hope that we learn a lot and that actually ends up helping these children. it also then allows us to imagine moving more towards a platform approach or a process approval, which I imagine being grouping many diseases together, coming up with common outcome measures. There’s a lot more in common than there is different between a lot of these diseases, certainly in the category of neurodegenerative diseases. A lot of kids that have different diseases look a lot like Mila. So, I don’t want to oversimplify it, but I do believe that it gets over complicated often by academics and companies when thinking about how to address this. They should be grouped together and instead of bringing one car over the bridge at a time, we need to be bringing a bus with a number of different ones back and forth across. Otherwise, if we have to go one at a time, it will never scale, and it’s got to become faster and cheaper and better while being safe.

Daniel Levine: You talk about a regulatory system that was built for larger market drugs than these individualized therapies. I’m wondering on the manufacturing front, if we have a bit of the same problem. Do we need to rethink how these therapies are made and stored? Is there some scale down manufacturing that might be possible perhaps at centers of excellence rather than conventional CROs or drugmakers to scale this?

Julia Vitarello: Yeah, that’s a good question. I will preface this by saying that I am not an expert on ASO manufacturing. What I do know is that the manufacturing guidelines and the cost of manufacturing for ASOs is less of a problem, significantly less of a problem, than for other modalities such as CRISPR and gene replacement therapies or vectors. As I mentioned earlier, the costs and the requirements are not prohibitive right now. I do think that said, having an enormous facility that makes very large ASOs and utilizing that for small amounts that are needed for an N-of- one, that was a big problem with milasen because no one had done that before. So, finding a company to actually manufacture milasen was very hard because no one had made that small of a quantity before. Now things are changing and there’s maybe one or two companies, and I believe nonprofits, that are looking at small batch ASO manufacturing, but we certainly need to move towards rethinking what is really needed in a small batch manufacturing facility. And as this becomes more routine, I would imagine that it’s going to be that instead of having large equipment that’s made for large amounts of ASOs, there will be ways that are appropriate and safe to make this in smaller batches. Hopefully, that will drive the cost down, and the requirements for GMP may need to be rethought. We’re in the process of thinking of that right now, of what is proportionate and what is correct for this new paradigm for GMP—what does GMP look like for N-of-one ASOs.

Daniel Levine: While the N=1 Collaborative is initially focused on ASOs, it does talk about this as a starting point. Do you expect the work to expand into other modalities? And do you think the types of questions you’re seeking to answer about ASOs will be applicable to other kinds of therapies?

Julia Vitarello: Yes, definitely. I think that the, the difference between the N-of-one collaborative and other organizations or companies out there is that it is very focused on making individualized medicines, completely modality agnostic, routine and really accessible to anyone who can benefit from them around the world. So, ASOs are on the table right now that that’s what was used for milasen and that’s the realistic modality to be using right now. And there’s a lot of reasons why ASOs are perfect right now in the sense that beyond everything I mentioned about being programmable, they are well suited right now in terms of penetrating the brain very well in terms of their safety profile is pretty well understood. And even though we’re still learning about it, they really are a very good fit right now. However, in the N-of-one collaborative, we have leaders in the world of CRISPR and they are involved. They are participants, their voice is heard and needs to be heard because as we continue to push forward, even though ASOS are the first modality, we have to be thinking about what is right behind us. And that is CRISPR, that could be other RNA therapeutics in the future, there could possibly be gene replacement therapy, which we’re not at right now, but that could certainly be discussed at some point. So, there are other modalities right behind us. As we pave the regulatory path, it’s a fine line between talking about a pilot about ASOs, which makes sense because you have to start somewhere, but also keep in mind the bridge that we build. In some ways, Mila was kind of like a rope was thrown over the river and we pulled Mila across. Now the N-of-one collaborative is building the bridge. We need to make sure that the bridge that we’re building, which is going to be maybe one lane to start with, and there’s one car at a time being brought over by an academic. We need to make sure that that bridge is in the right place. We’re building it in the right place. We need to make sure that it can move from one lane to 50 to a thousand lanes. And we need to make sure that it can withstand not just one car going back and forth, but buses and many of them. So, I think it’s important to make sure we always consider, and we are doing that in the N-of-one collaborative, like I mentioned with CRISPR specifically—that we’re always thinking about the fact that this needs to be a modality agnostic, patient agnostic, a mutation agnostic approach.

Daniel Levine: After losing Mila, I can imagine an impulse to step away from the world of rare diseases. You continue to serve as CEO of Mila’s Miracle Foundation and help establish the N=1 Collaborative. What drives you to do this?

Julia Vitarello: Yeah, a good question. You know, my life was ripped apart by everything I went through with Mila leading up to her diagnosis. Even with milasen, I went from being told my daughter was going to die to then within a year being given this incredible hope—a caveat here is that the expectations were set very correctly by Dr. Yu and his team. We knew it was a long shot, but also it looked very promising. In fact, in the first year it stopped Mila’s disease and there were lots of improvements. But then from there it went crashing down. When I saw that after three years it wasn’t stopping her disease and that she was having some problems like her hip coming out of her, the socket of her hip, because of Batten disease. That ended up in pain and forced a lot of very difficult decisions at the end of her life. So, I’ve been on this rollercoaster ride and over the course of this, because Mila’s story has been in the spotlight, I’ve gotten to know just an enormous number of rare disease parents across many diseases. And I hear from the ones that have children with neurodegenerative diseases, and of course I can relate to all of them and listening to the stories of their children getting worse and worse and not being able to find treatments, even if the treatment might be there. I hear stories of biotech companies shelving rare disease treatments right before they’re going to start them or after they’ve begun because they don’t meet what they consider to be the expectation of “probability of success,” even if maybe that’s helping children live longer, and it’s just such a devastating world of rare disease right now. I see a lot of hope and promise, but I also see a lot of broken pieces, and I see in the case of Mila and the case of individualized medicines the current way we’re going right now of working gene by gene and these massive hurdles that have to happen in order to give access to children who are dying or have lifelong debilitating diseases. There’s just so many things that are not ethically okay with me. And I feel an enormous sense of responsibility that I’m not fighting for my daughter anymore, but I am fighting with her right by my side, because every day I have moments where I cry. I am learning to live, I’m divorced. I have my son half of the time now. So, instead of having a family that’s doing happy, fun things in Colorado, I have, my daughter who has died, I have an empty bedroom of hers, and I have an eight-year -old son who I see half the time. I see all of these millions of families out there where little to nothing is being done for them because they’re not commercially viable and they have to start foundations and raise millions of dollars. So, I just feel an enormous sense of responsibility to do my part in this, which is not going to fix everything, but it is to say, “look, there really are millions of people who could eventually benefit from an individualized medicine approach, which Mila’s story has shown as possible now.” And we know that diagnoses are going up and that more and more and more, especially children, but adults as well are being diagnosed with rare diseases. Even those that are not fatal, in some ways that’s even harder because for the rest of your life or decades, that entire family will never be able to live a normal life in many cases, nor will the child. I look at it and it seems to me that it’s not acceptable and it’s not okay that we have the technology, and we have the patients and that there is not access between the two. And so I would like to do my part to be part of the various solutions to making that happen. One of them is the N=1 Collaborative, which is fundamental. I try to do my part at complementing the voices of the incredible scientists and researchers and doctors that are part of that. I am part of an initiative to see if there’s a viable business model, which is extremely difficult right now. Once again, I am not a biotech CEO or an investor, but I do my part to make sure that we are doing the best we can to make that viable business and reimbursement model possible. And then, I’m doing my part in trying to make sure that this regulatory path, that they really understand how fundamental this is. This concept of Mila to millions, we really need to understand that it’s not morally okay that we’re not giving access to this. And we have to come up with a path, whether it be a modernized or entirely new regulatory path, and it cannot happen in five years or 10 years, it needs to happen now because we’ve been talking about it for four years. So, I’m trying to do my part in these three different solutions to the problem, and I just feel a huge responsibility. I was given that because of my daughter of Mila and she opened up this world to me and she fought hard, so I can fight too. That’s why I’m still in it.

Daniel Levine: Julia Vitarello, CEO of Mila’s Miracle Foundation and co-founder of the N=1 Collaborative. Julia, thanks so much for your time today.

Julia Vitarello: Thank you, Dan.