TIMOTHY CURRY: We are delighted all of you have joined us today on Rare Disease Days for a very special Center for Individualized Medicine Grand Rounds. My name is Timothy Curry, and I'm the William O. Lund and Natalie C. Lund program director for clinomics and the Midwest associate director for practice implementation for the Mayo Clinic Center for Individualized Medicine. The CIM Grand Rounds lecture series highlights the latest in scientific discovery, innovation, and shares how individualized medicine is being translated into practice to transform patient care. I know today's presentation expert panel is going to accomplish exactly that.

Rare Disease Day, today, is celebrated on the last day of February to raise awareness and generate support for everyone who is on a rare medical journey. This year it falls on February 29, the rarest day. First celebrated in 2008, Rare Disease Day provides the energy and is a focal point to enable rare disease advocacy work to progress on the local, national, and international levels.

It's my pleasure today to introduce our Rare Disease Day featured speaker, Julia Vitarello. In December of 2016, Julia founded Mila's Miracle Foundation, and in just a few minutes, we're going to hear the journey that led to the creation of this amazing organization. Through Mila's Miracle Foundation, Julia has raised millions of dollars to fund novel treatments and programs for children with rare genetic conditions. Julia has also co-founded the N=1 Collaborative, which serves as the international scientific hub for medicines, as well as EveryONE Medicines, a biotech aiming to prove a viable business model where there is currently not one.

Additionally, Julia co-runs the first ever single cell atlas of pediatric disease with Boston Children's Hospital, funds basic science research in the US and Europe, and hosts meetings with industry experts and families in the rare disease community. It is an honor to have her join us. Now please join me in welcoming Julia as she presents on Mila to Millions.

JULIA VITARELLO: Thank you, I appreciate that. And thank you to everyone at Mayo for taking the time to listen to my story on Mila, my daughter, and my thoughts on this emerging field of individualized medicines, which my daughter's story has opened up. Before I tell you any more, though, I do think it's very helpful to get to know my daughter a little bit. And so we'll start with a very short three minute video that allows you to see who Mila is.

[MUSIC PLAYING]

MILA MAKOVEC: You are my sunshine, my only sunshine. You make me happy when skies are gray.

JULIA VITARELLO: So our daughter's name is Mila Virginia Makovec. She was born on November 5, 2010. When I think about Mila as an infant, I think about smiles and laughter and health. And--

ALEK MAKOVEC: Half an hour after she was born, she was strong enough to hold on to my finger and I could almost pick her up off the bed. And--

JULIA VITARELLO: When Mila was a toddler, she was a climber. She was a hiker. She was a runner.

How old are you, Mila?

MILA MAKOVEC: Three and a half!

JULIA VITARELLO: Here's our sugar-high daughter.

Slide, slide, slide.

ALEK MAKOVEC: Very physical. Always loved to ride a strider.

JULIA VITARELLO: Nice, bug.

ALEK MAKOVEC: Play in the snow, go sledding.

JULIA VITARELLO: Coming.

[MUSIC PLAYING]

We noticed that Mila was getting stuck on her words. She would say, mommy, mommy, I have to, mommy, I have to, and not be able to continue. And then suddenly, around three years old, we started noticing that her feet were slightly in-turned and she was walking strangely. And then at four years old, we noticed that she pulled books in close. And then around five years old, Mila's feet started moving really quickly in this strange pit-pattering way, and then she would fall back on her butt. And every time she stood up, she would fall back and stand up and fall back. You know, we took her around to different doctors who never could really figure out what was going on with her. And then time passes and then in just one month, everything can change. She could no longer see anything.

What's brought her so much happiness is playing with her toys, and looking at her books, and watching TV, and playing with her brother. And suddenly it looked like she could no longer play with anything. It's so hard to see such a outgoing little girl not be able to play with other kids, and not be able to play with toys, and not be able to watch Elmo anymore.

[MUSIC PLAYING]

I still watch that video. I've watched it hundreds of times, and it really, truly feels like I'm watching the story of someone else's life, even though I've lived it. You know, I became a mother kind of like anyone else did, in the sense that my daughter was seemingly very healthy. She was very outgoing. She was very agile, very sporty. We live in Colorado, so she was skiing when she was two years old, and going to the top of the mountain. She was rock climbing 40 feet. She was jumping from the couch to the coffee table and back and forth and running around the house singing all of her favorite words to Puff the Magic Dragon and all of her favorite songs.

And when she was about three and a half, she started having sort of strange symptoms, but they were very subtle to other people. And they started building up over time. And between three and a half and six years old, I carried around a little scrap piece of paper in my pocket that said neurological symptoms with a question mark on it. And honestly, I barely knew what that even meant.

I just started seeing my daughter first have problems with tripping and falling, and she had been so agile before. And people said, oh, she's just clumsy. But she had never been clumsy before. She was started to be covered in bruises. I remember having a big bruise on her eye, big bruise on her arm, bruises all over her legs. She had stepped on all of her toys and books in our house and everything was broken. And it was my first child, so I didn't know if this was normal or not. And so I started bringing her around to all the different specialists.

And she started having problems seeing and the ophthalmologist had said, don't worry, you know, she just probably needs glasses. Her feet started in-turning. They said that can happen. It'll correct itself over time. She would stutter and get stuck on the first few words of her sentence and get stuck on the word mommy, which was really hard for me because she could never get past that word. And it was driving me actually crazy, and I was trying to help her, but she could not get unstuck.

And the stuttering therapist said that 25% of children would grow out of that, you know, have that and then grow out of it. And by the time she turned six years old, things had gotten-- there were too many different lists on my little piece of paper that said neurological symptoms. And I found myself crying on a regular basis. And I knew that couldn't be a good sign. I was really tired of having so many people tell me that I was crazy.

I'd been to a hundred doctor and therapy appointments, often lugging my newborn son at some point along with me across the country. And at some point at six years old, I remember I looked for another neurologist because I couldn't get any answers. And they told me that it was going to be six months wait. And that day I gave up and I packed a duffel bag. I went into the ER at Children's Hospital Colorado, which was near my house. And I figured there was no way they could let her out unless they figured out what was wrong. And they kept her for a week. This was the end of 2016, so it wasn't maybe as simple as doing a genetic panel right away, after which they did end up doing genetic testing.

And it came back with an answer, which I will tell you that immediately I was incredibly relieved. Like, I'm not crazy, there is a cause. And if there's a cause, I must be able to fix it. It took me not very long, 10 minutes, to Google and read about Batten disease, which she was diagnosed with in the very rare form of already rare Batten Disease called Batten CLN7, to figure out that it was probably one of the worst diseases Mila could ever have. And I didn't know. I thought it was a well read person. I had no idea that a very typical healthy child could then be told that she's going to lose every single ability except for hearing and die in the next few years.

So, the only way to really describe that period, because it's very hard to find the words, is that, I'd just turned 40. Just my life as I knew it was over that day. I'm a very positive person, but none of the things that mattered to me mattered to me anymore. It's just, your child's health is everything, you know? So I did everything I could. I cried on the floor of my closet pretty much every single day. Tried to hide that from my children while I then rallied to play with them. And then, by night, tried to read science.

I had no idea what I was reading. I was reading white papers on Batten Disease and lysosomal storage diseases, and I reached out to every scientist and doctor I could until they actually responded to me. And I learned a lot in a very short period of time. In just a few weeks, I really learned that this was one of the worst diseases Mila could have ever been diagnosed with. I also learned that there was a tiny glimmer of hope at the time that we might be in time to stop genetic disease. But it was a glimmer. That's all I needed.

I started a foundation, Mila's Miracle Foundation. I didn't really know what a foundation was. I didn't know what a nonprofit was. I didn't understand the science. But I learned very quickly as I watched my daughter rapidly declining and losing her last words, losing her vision completely, losing the ability to swallow completely. And over that next year, I decided that I was going to fight for her as hard as I possibly could because she was still smiling and laughing and fighting.

I started down the pathway towards a gene replacement therapy because there was little to nothing known about the Batten CLN7 gene or MFSD8 gene. And that got me going, and that did eventually become a gene therapy. But I knew it was going to take many, many years and many millions of dollars and not be in time for Mila, at some point. I realized that.

Along the way, Mila's story took a turn because it's autosomal recessive. They could only find one of the two mutations, and I had many labs look and none of them could find it. I was fortunate enough through a plea on, of all places, Facebook to see if there were a lab that did whole genome sequencing would be willing to dive deeper and try to find Mila's missing mutation. I was afraid that I was going after the wrong gene and I was going to spend all of my time and energy raising money and trying to save Mila's life and go after the wrong gene and that she might have a different disease with one mutation in this MFSD8 gene.

I also was terrified of losing my son, and I wanted to be able to fully test him. And being able to only test one of the two mutations was not OK with me. So I really pushed hard for that, and that led me to Dr. Timothy Yu at Boston Children's Hospital and his lab, who unbelievably, just really stepped up to help me try to find the answer, really, truly, just to help with the diagnosis.

Along the way, as they stared at a screen because they could not find this missing mutation for a long time. They looked day and night, weekends for a month. They ended up finding the mutation that was a deep intronic mutation that was very unusual. And they not only were able to call me and tell me that they had confirmed that it was Batten CLN7, but that my son did not have the same disease and I wasn't going to have motherhood ripped from my arms, which was something I could barely sleep at night for numerous months until we got that answer.

And that same call. Dr. Yu also said, you know, we have an idea. There's been a drug called Spinraza that's been approved for spinal muscular atrophy, another terrible disease which I don't need to tell all of you about, as you probably know how horrible it is. And what a game changer Spinraza was. It had just been approved a month before by the FDA, and it was on everyone's minds, especially the neurologist that we're working with, Tim Yu. And it gave them an idea of creating an ASO or antisense oligonucleotide similar to Spinraza for Mila.

The problem was that they searched far and wide and there were no other patients that shared her mutation. And, as you can imagine, a number of people said, that's crazy. How could you ever do that? How could you make a Spinraza-like drug just for one person? But thank goodness Dr. Yu and his team continued forward. And over the course of that next year, as Mila rapidly declined, they designed and manufactured and tested in a way that had never been done before, a drug for one person. And they named it Milasen after my daughter.

Within one year, we moved to Boston and Mila was receiving this antisense oligonucleotide called Milasen, which I didn't know about, actually, that it was even named that. I didn't even really fully understand what a big deal this was until I think I moved to Boston and started, you know, talking with doctors and scientists. And there were tears in their eyes and they were crying to me about that they couldn't believe that this was happening in their lifetime.

Mila did unbelievably well the first year, I really had no idea what to expect. I knew that I had nothing to lose in the sense that this had been a modality that had been around for 30 years and tested in animals and more recently in humans. And the risk of not treating Mila was black and white. She was going to lose all of her abilities and die. The risk of treating her was a modality that had been around for a long time, and it was showing really great promise in the lab, restoring health to her cells in three independent labs. So it was a no-brainer for me.

But I didn't really know what to expect. And in that first year, despite the fact that Mila had lost her vision, she was having seizures 30 times a day. She was no longer eating by mouth, but by G-tube. She was smiling and laughing less than before. In that first year, we saw, maybe subtle to some people, but incredible to me, changes in the sense that she was pretty much seizure free. She occasionally had a little myoclonic jerk, but she went from 30 down to pretty much zero or one tiny little short seizure. She was sitting up straight. She was holding her body up so I could hold her from behind, and she could take steps, even alternating up the stairs sometimes. She had stronger legs.

She was eating by mouth. It wasn't perfect, but it was pureed foods. But it was a lot better than just by g-tube. And most importantly, she was just laughing and smiling at the times that she used to and the funny books and songs that I would read and sing to her. You know, crying babies and Santa Claus sneezing and stuff. And she was doing it more than she was before. And that was probably the most meaningful thing to me.

In the second year on Milasen, it was unclear whether or not her disease had been kind of stopped or if it was slowly kind of taking over. It was hard for me to look back and remember. But our life was very not dramatic. She was still virtually seizure free and generally happy, despite having lost a lot. And she was at a very progressed state when she began Milasen.

And then, in the third year, I could tell that the disease was continuing. And it was something that Dr. Yu had set correct expectations for me. He had explained to me at a time when I didn't really understand all of this that Mila's neurons were dying and that some of them would have already died going into Milasen. Some of them were dying, and we might be in the process to stop them. And some of them were dying and we might not be in the process to stop them.

And that does feel actually pretty accurate in the sense that, Mila, there's no doubt about what a dramatic effect Milasen had on Mila. But she was very progressed and probably a lot of her neurons had already died, or already accumulated a lot of lysosomal storage and too late to be helping some of those neurons.

At the end of the third year, I was faced with decisions that I still can't believe any parent, ever, anywhere in the world has to face a decisions I had to face for my daughter who could not see. She could not talk. She could not take a fly off of her nose, and her brain was starting to atrophy. It had not been during Milasen, but it continued, which is part of Batten Disease. And I was just forced with decisions that, yeah, no parent should ever have to make. And three years ago, my daughter's very big spirit left her very tiny body, and it's been just unbearable.

I'm a positive person. I have so many great things in my life. Thank God I have my son. But it's still something that I don't understand, how any parent anywhere loses their child and continues living. It's a part of the rare disease story that isn't often really talked about, so I try really hard to make sure that I always talk about this. Because you hear about the child being diagnosed and a parent maybe taking care of them or fighting, but you don't really hear how hard it is to live the rest of your entire life without your child physically there.

And the reason that I am here right now is because this wasn't in time for Mila, but it showed what's possible. And it's a big deal, and I've been very fortunate to be part of thousands of conversations because Tim Yu and many others, including many at Mayo, have included me in these conversations around the science, the regulatory, the reimbursement, everything possible. I've learned a lot. And what I've learned is that while it wasn't in time for Mila, it showed what's possible.

Her story showed that we can now find the underlying genetic cause, and we can design a medicine to treat it, even if it's unique to one person. And I know that that's an incredibly different paradigm to how we've been developing medicines and treating sick children in the past. And for me, it's allowed me to listen and learn and look at the big landscape and think, how do we change things right now? How do we allow for exponentially more children to be able to access medicines?

And the way I think about it is, statistics are not great in rare disease, but we have to go with what we have right now. And global genes points to 60 million children that will die before the age of five from a rare disease. I lived in Italy all of my 20s. That's the population of Italy. That number does not include Mila, who died at 10 years old. It doesn't include children with lifelong debilitating diseases. It doesn't include adults.

This number is massive even if it's not correct. And let's say it's, instead of 60 million, 40 million or 20 million or 10 million. That number really actually doesn't matter to me. It's tens of millions of dying children on one side. And I see the names of them listed and this long list on the left side. And on the right side, I see what used to be sort of like an empty toolbox. And all of you know this more than I do. I don't want to ever pretend to be a scientist or a physician, but I do realize there wasn't really any hope for these people. But now there is.

And now there's a toolbox with modalities like antisense oligonucleotides, a lot of which are programmable, meaning that the process kind of can stay the same. And what does that mean? How do we create access between the patients and the modalities? Right now, that depends on luck. That luck is whether or not you're part of a large enough disease to be commercially viable or you have a Herculean effort from a parent and a clinician who are willing to do what I did and fight for that child.

So access depends on luck. What about everyone else? And I think the way I think about this is that the current system, or if we want to call it a house, let's say, of drug development, was never designed for this paradigm. It was designed for one drug for, tens or hundreds of thousands of people. Now, Mila's story points to this future of maybe the opposite, right? Maybe it flip flopped, of tens or hundreds of thousands of drugs each for one, or six or 20 or 100-- small numbers of people.

Especially as rare disease, we're starting to learn in Mila's case, the underlying genetic mutation was unique to her. So another way of thinking about it is instead of categorizing patients maybe by disease and with rare disease, you end up with 10,000 different diseases. And it will take us thousands of years if we go do business as usual like we're doing now to cure, treat and cure those diseases. But if we think about them perhaps by mutation, for example, that's just another way to categorize. You look at a splice mutation like Mila's, and that is amenable to a splice modulating ASO. So now by categorizing that differently, you can now think that the approach for Mila is applicable across many, many diseases.

And that should also change things like the regulatory path as well. That's obviously a critical, critical place that we need to change. So we have the children, we have more and more children as we diagnose them and early and earlier. We have these modalities more and more. They're not perfect, and many of you, thanks to you, are allowing for these, you know, modalities to mature and have more and more modalities, let's say, in that toolbox. And this is a bold thing to say in front of all of you, but I would say what I've learned from all of you and from others is that we're in a really unique time where science is not the limiting factor, meaning we still have to do all the science. Without it, we'll never get there. That's the center of everything. But before, I've learned that we couldn't find Mila and we certainly couldn't treat her.

But now we have the technology to find Mila. If we wanted to, we could find all the Milas at birth, and we could treat, not all of them yet, but there's a good percentage of them that can be treated. And with time, we'll have more and more tools and that percentage will go up. So we have the technology to find Mila and to treat her today. And what we don't have is we don't have the infrastructure and the processes that allow for that access to connect the children with treatments. And by that I mean, obviously regulatory. What does that mean? In my mind, we're going product by product. We're doing product approvals.

We can't do that. If we have to go through what we did for Mila, which is currently six years later, just as hard, if not harder. It takes year or years. It takes 50 to 100 or more people involved, from academics to companies to families, et cetera. It takes a thousand-page IND. It takes millions of dollars. This is not replicable. This is not sustainable. And we still, six years later, are doing this. And in fact, I actually think it's getting harder and slower and more expensive. So something is not working.

And there's a lot of great people out there who want to do this. The N=1 Collaborative, which, Tim Curry, you mentioned earlier, which I helped start together with Tim Yu and some others, has now 500 members of which, you know Margot Cousin-- thank you for inviting me, by the way-- from Mayo is part of as well as others. And 500 people raising their hands around the world to say, we want to do this and really want to learn how to do this, or already actually working in this field of individualized ASOs to start with. 500 people. That's a lot.

And so you have all these eager people who want to actually help. You have the patients. You have the modalities. We don't have the correct regulatory path. We need to be able to shift towards sort of a process approval instead of a product approval. And to do that, of course, we need the data and learnings from each of these patients, starting with Mila's shared, which is the concept behind the N=1 Collaborative. But we also need regulators and everyone to start thinking differently about this.

And I do think that the foundation, if you want to call this house the drug development house, we've been trying to renovate it to fit this paradigm. And I personally don't think that renovating or modernizing the current house is working. And I do think we almost need to just accept that house might work for large indications, which is what has traditionally been how we've approached disease. But now we need to build a house next door.

And when we build that house next door, which I think needs to happen urgently and right now, I think we need to pull from regulatory flexibilities in other areas that allow us to move towards a process approval that may be looking more at accredited partners along the way, not so dissimilar from neurosurgery. Many have claimed that Milasen fell between drug and sort of neurosurgery, a hyper individualized approach-- and some of you listening may be part of that world-- is that in some ways it fell in this no man's land between. There's a lot to say about that, but I don't have time to talk about. But I do think that thinking that way and starting to think about things a little bit differently, we need to pull from that in order to really, really, truly, greatly shift the regulatory path and move toward this sort of process approval.

I think that we also need to think about reimbursement. I think that the regulatory path is half of the battle of access, but this must be, in my mind, not only reimbursed, but I believe there need to be companies in this space working with the academics. There needs to be a collaborative model where each brings their expertise to the table. Why? Not because I don't think that academics can do it. In fact, thank goodness they are because we wouldn't be here without them, and they're the only ones pursuing drugs like Milasen right now. But there's been 12 or 14 treatments in the last six years because there's only so much with this many people and amount of money that's needed, and time, that the amazing academics that are leading the way can do this.

So we need to bring more companies in to be able to do this at scale because the numbers of children that need to be treated are so enormous that we have got to be able to do this in a much more scalable way. And therefore, that also means allowing for reimbursement of these drugs. Otherwise, it's parents selling lemonade and cookies and raising millions of dollars. And that's not acceptable and it's not scalable.

So all of this to say that I do see hope. I've found great alignment in the UK for many, many reasons. And we have started a pilot in the UK to actually create a model for exactly this. Of how do we drastically shift the regulatory process to process approval where you can push, many, many, many individualized, starting with ASOs, but many individualized medicines through without having to stop every single step of the way for every single molecule?

We plan to be able to learn how to do that over the course of treating patients over the next few years as well as how do we come up with a reimbursement model. And my hope is that will prove a model which can greatly help other countries because I hope this is eventually throughout the world. This is not just about the US or the UK. I hope that this creates a model that kind of unravels the rest of the world and shows a very different way of doing this.

So I leave you with my thought, which is what I go to bed with every single night is how do we get from Mila to Millions? It's the name of my talk. It's really how I think about this is, we have the ability to do this. The question is, will we? And that is a moral imperative and an ethical question. And all of you guys are playing in an unbelievably important role in this. But I think it requires all of us to shift the way we think. And together, I hope that if we're here again, maybe not in a year, but in two to three years, that we see exponentially more children, dying children, treated. So thank you very much for inviting me to tell Mila's story and my thoughts on this. And I'm happy during the panel discussion to answer any questions you might have.

MIRA KEDDIS: Thank you so much, Julia, for a really inspiring story and instilling in us a sense of resiliency and innovation. Thank you. My name is Mira Keddis. I'm the Director of Education at the Center for Individualized Medicine, and I will be co-moderating the second segment of our talk with a panel discussion with Dr. Laura Lambert will be co moderating with me. She's a director of the Mayo Clinic Functional Omics Resource Lab. The lab designs and executes functional genomic studies across Mayo Clinic.

We welcome our panel members. Ms. Erica Barnes. Ms. Erica Barnes is the executive director of the Minnesota Rare Disease Advisory Council, which is a Minnesota State agency created in 2019 after grassroot efforts by a cross-sector coalition of advocates. She has over a decade of advocacy and nonprofit leadership experience and has co-founded, with her husband, Chloe's Fight Rare Disease Foundation in honor of her late daughter. Ms. Barnes also chairs the NIH-funded Global Leukodystrophy Initiative Clinical Trials Network patient advocacy consortium.

Our second panel member is Dr. Margot Cousin. Dr. Margot is an assistant professor of medical genetics in the Department of Molecular Medicine. She's the director of the NR1 therapeutics program in the Center for Individualized Medicine. She's a KL2 Scholar and completed her PhD in clinical and translational science and postdoctoral training in translational omics program with the Center of Individualized Medicine. Her research focuses on developing and translating novel therapeutics, such as antisense oligonucleotides for rare genetic disorders.

And last but not least, we have Dr. Radhika Dhamija, who's an associate professor of Medical Genetics here at Mayo Clinic in Rochester, and she's a consultant in the department of both clinical genomics and neurology and dual boarded in both neurology and genetics. She's the associate program director of medical genetics and genomics residency, and she has interests in neurocutaneous disorders and is the co-director of neurofibromatosis clinic at Mayo Clinic. the

So I'd like to start with our first question. I'd like to ask Dr. Erica Barnes to comment to us about her perspective from a state agency standpoint in terms of where do you see the opportunities for currently available treatments for rare disease patients? What does that look like from a policy perspective?

ERICA BARNES: First of all, thank you so much for having me. This has been so wonderful. And Julia, thanks so much for sharing your daughter's story. I often meet other fellow mothers, and your story is my daughter's story. And we know that this is the story of so many individuals with rare diseases, and this is why I got involved in the work.

Yeah, so from the perspective of now being someone who is the executive director of a state agency and kind of having a policy lens, what I would say is, I think that what Julia was saying in terms of needing to make paradigm shifts not only in the research landscape but also in regulatory landscape, I would say that we also need to make those shifts in the policy landscape.

And one of the things that really struck me when you were talking is, so many of our patient communities, mine included, we work so hard to, as you said, you're lucky if you're able to raise enough money or if you find that researcher that happens to be able to work toward a cure or an effective treatment. And then you get to the FDA, and maybe even at the FDA, you have that regulatory flexibility for clinical trial design. But what good is it if all of that flexibility then hits, let's say, a state formulary committee and those policies don't accommodate some of all of that flexibility.

So from a state agency standpoint, one of the main things I want to do is help the state understand that what's common sense for common diseases isn't always common sense for rare diseases. So we need to make sure that our drug formulary committees understand if there's a novel clinical trial design and not exclude patients based on that. And then also really working, and I know that this is something that all states are struggling with, but really understanding how do we prepare ourselves for the future for reimbursements?

Our reimbursement structure, especially in Medicaid, is really designed for chronic diseases, for pain costs, for diseases over time. It's not designed for these one-time curative treatments. So one of the things that we as a state agency are working toward is really helping the state understand how do we restructure those reimbursement pathways and models for a sustainable future.

LAURA LAMBERT: Fantastic, thank you. And thank you again, Julia, for sharing your story with us. It's the reason we're all here doing what we do, and it's so inspiring. The question for Dr. Cousin-- Margot, could you speak to what we're doing at Mayo Clinic specifically to further individualize treatment and rare disease therapeutics?

MARGOT COUSIN: Yeah, absolutely. And yeah. Thanks again, Julia, for coming. You're such a great speaker, and to hear your story and share it with this community I think is really important.

So, as you might imagine, Mayo sees rare all the time, so I don't want to pretend like it isn't something that we don't do here every day. We do. But when we think about these really ultra rare conditions and really severe patients, I think, again, there is that opportunity that you speak of, Julia, that we have the ability. It's just a matter of figuring out how to get there.

So, within the Center for Individualized Medicine and in partnerships with our many different clinical departments, we're trying to do more, and we're trying to get organized and use our resources wisely to get patients to the right therapeutic opportunity. And maybe that's working in my lab on patient cells to try to devise a therapeutic strategy, or working in Dr. Lambert's lab, or collaborating with another academic somewhere else, or a foundation. Putting all those pieces together to try to figure out what that path is to go from a single patient or a small number of patients to a clinical trial. And those are a lot of different pieces.

That involves clinical trial readiness. That involves biomarker discovery. That involves all this in addition to just thinking about what that drug might be, establishing disease models. All of these steps need to come together. So we're really thinking hard about these different components or modules of work that needs to be accomplished to go from A to B to get to that finish line. And there's a lot in there.

But as we get more organized and continue to pull this rare disease community, which is a really fantastic, motivated, and collaborative community together, I think as those policy changes come about that you all are talking about, that need to change, I'm hoping that we'll be ready to implement the strategies that we have so that we're ready and not fumbling when it's time to hit go. So those are some of the things that we're working really hard to do.

MIRA KEDDIS: Thank you, Dr. Cousin. Next question is for Dr. Dhamija. We heard from Julia that the fight to know what the diagnosis is and maybe a temporary relief that you felt knowing what your daughter has is just knowledge of affirmation that there's an explanation. How are we doing right now in terms of diagnosing rare genetic disorders? Where are the advances in diagnostics?

RADHIKA DHAMIJA: Yeah. Thank you, Dr. Keddis for the question. I want to echo what everybody said, Julia. Thank you for your talk. I've heard you talk many times, and it's always a pleasure to hear it over again.

So I think we've come a long way in terms of being able to diagnose genetic disorders or rare genetic disorders. So over 80% of rare disorders are genetic in nature. And I think the first step is typically phenotypic-driven testing. Next generation sequencing technology has enabled us to offer these panel testing that Julia did mention took a while for her daughter to access, now, very quickly. And whole exome and whole genome sequencing have become quite routine for us when we're dealing with complicated patients, either with phenotypes that we think are genetic but don't quite fit into a syndrome. And not only in the outpatient setting, but we're offering whole genome and whole exome sequencing to critically ill infants in the neonatal ICU and critically ill pediatric patients in the peds ICU, and sometimes even on the floor when we're trying to get to a genetic diagnosis early.

I would have to say then when we were talking about rare disorders several years ago, we would say that time from when the symptom onset to a diagnosis were sometimes over a decade. That number is still long, but it is about five years now based on global gene review. But I think there is certainly a disparity. So patients who have access to big academic centers often get these testing first line and diagnoses like Julia pointed out, can be made at birth. The technology is there, and some academic centers are perhaps pushing it a little bit more than others. So there's clearly a disparity. But I think we've come a long way. We can find Milas every day, and we are doing it in our clinic. It's just what happens after that.

I think for some families, it is an end to a diagnostic odyssey. For example, Julia said that for a second she did have a relief that it was not in her head, but her daughter did have real symptoms. And I think we hear that from most families that they went doctor to doctor before somebody said this could be genetic and let's run this testing. So for some families, it is end to a diagnostic odyssey journey, while for others it does open up doors to potential participation in clinical trials. Or if they are lucky and they fall into that 10% of rare genetic disorders that have therapeutics in the pipeline, they could be connected with the right people where their therapeutics may be an option or clinical trials may be an option.

So I think this field is moving fast. Diagnosis is certainly happening much quicker now and then we are doing a lot to be ready to then translate it into therapeutics with the help of certainly academia, industry, patient advocacy. Very, very important.

LAURA LAMBERT: Thank you so much. That's a lot of really good points there. The next question is for Julia. You mentioned in your talk you spoke about a model in the UK that's been adopted over there. I think we'd all be really excited to hear more about what's working.

JULIA VITARELLO: Yeah, I'm happy to, Laura. I noticed about a year and a half ago that it seemed that the stars were aligning in the UK, in my sort of humble opinion at the time, that might be the right place and the right time to scale what we've done for Mila there, for the reasons that the former prime minister's son died of a rare disease. That changes everything. In fact, I think that if tomorrow all the people in positions of power, unfortunately had children diagnosed with Batten disease, things would change pretty much overnight.

That changed the mindset of the UK, I think, when that happened. This was David Cameron's son who died at a very young age. It really hung their hat on genomics. They obviously have lots of wonderful academic centers, some biotech as well, in the rare disease space. But really also I think that the MHRA, the regulatory body, really has a very interesting take on what they need to do to change and how they interpret protecting public health. It was something that really, really resonated with me.

So very obvious that protecting public health is protecting all of us from scary drugs like thalidomide. I understand that, and everyone kind of gets that. But to have the MHRA in my first discussions with them starting a year and a half, two years ago, say that another definition of that is to ensure access and actually rapid access to technologies that exist today maybe seems small, but it's revolutionary in the sense that that's where I was getting stuck. Like, hey, there's Mila, and then there's these technologies, and there's lots of Milas. How is it that it seems to me that the regulators are, maybe not purposefully, but are impeding access by continuing to use the same regulatory guidelines and pathways? More or less. Some adaptions, but not quite enough.

And the MHRA really gets that. And they were very, very motivated, especially to be honest, post-Brexit as well. Being independent is not a minor thing. They are not attached to the US, very conservative FDA or perhaps somewhat conservative Europe as well, and they're independent. They also have one system where all of their clinical-- the NHS, they have all their clinical and genetic data in one place.

And then what really got me there physically and got me there to start meeting with each of the different players was that Genomics England is just a really fascinating model. If any of you know it, it's a company but owned 100% by the government. And their job was to do genetic sequencing for the NHS. And then obviously it's up to the clinicians in the NHS to decide what to do with that. But they spent the last 10 years whole genome sequencing hundreds of thousands of people, and now they're moving into a newborn program right now. And I think they're kind of leading the world in a way of trying to solve the first half of the problem.