 Hello everyone, my name is Liliana, and I will be talking about personalized medicine. Personalized medicine is when it's a therapeutic approach where you develop a drug or a treatment that is specific for that one person. And I'm going to talk about personalized medicine using the example of the first case of a personalized treatment. And this was done on Little Mila in 2018, so quite recently. So, Little Mila, she was born a perfect, healthy baby. She was very active jumping around on her furniture back and forth. But however, by the time that she was three years old, her right foot started turning inwards. At four, her parents noticed that she was not seeing very well. Then at five, she started having this tumbling movements with her legs, and she started keep on falling. At six years old, she was practically blind. She could not speak so well anymore, and she could not control her movements, and she was having trouble swallowing. Her parents got worried, obviously, and they went to many doctors trying to find what could be wrong with Little Mila. First, they did some brain scans. And on the scans, they found out that Mila's brain is slightly smaller than what would be expected for a girl of her age. They also measured the brain activity, and they found out that Little Mila was suffering from many seizures day and night. And these seizures were getting worse as she got older, and by the time that she was six years old, she was having 30 seizures a day. Traditional blood tests revealed nothing that could indicate what is wrong with Little Mila. Parents were getting desperate. Finally, there was one doctor that he thought he knew what was wrong with Mila. So he took a little piece of the skin of Mila, put it under a very powerful microscope, and looked at it, and he found out that Mila's cells had these dense structures inside of them, and these structures are not normal in our cells. But they are characteristic of a certain rare disease, and in 2016, Mila was finally diagnosed with Patton's disease. Patton's disease, I think the best way to describe Patton's, is to use the words of Mila's mother, where she says that Patton's disease is a combination of Parkinson's, dementia, epilepsy, plus blindness. So it's quite a drastic disease. More on Patton's, it's a rare disease out of the 2.2 billion children that exist in the world, approximately 20,000 suffer from this disease. The fact that it's so rare might explain why it took so long for the doctors to diagnose Mila. It's a neurodegenerative disease, which means that it affects the brain and the eyes. It's genetic. It's a small mutation on a certain gene that makes the cell not able to produce an essential protein that is necessary for the cell to recycle old proteins and old fats. These old proteins and old fats cannot be recycled, so they accumulate in the cell. They form those dense structures that you saw, and the cell will end up dying because it's full of waste. Moreover, there are about 14 mutations that we know cause Patton's, and the one that Mila has is called CLN7. Mila's type, you can see the first symptoms at three years old, and by the time that the child is 11 or 12, she will die. So it's quite a fatal disease. But Mila's genetics are quite important, and they are the key for her treatment. So let's go a bit more into the genetic part. All of us have two copies of one gene. We inherit one copy from our father and one copy from our mother. The two copies of a gene system is brilliant, because if there's something wrong with one of the copies, you always have the other copy as a backup. So in Mila's case, she got from her father the common known Patton's disease mutation that is CLN7. She inherited from her father. The father has the second normal copy, so then he does not have the disease. But Mila has the disease, which means that the other copy must have also a defect. But the doctors could not find what this defect was. It was not something that they had seen before. So they went and they scanned the entire genome of the entire family, trying to find where the mistake was. And they found out that Mila had inherited a disease gene also from a mother, where the mother had a very random, rare mutation that they had never seen before. And this mutation causes a splicing mistake that makes the gene not work. So in the end, she has both copies that are wrong, so she is suffering from the disease. Now, what is this splicing? Splicing is both the reason why she's sick, but it's also the reason why she managed to get a therapy. When we usually speak about how genes make proteins, we usually go about something like this. We have a gene. The gene has DNA. DNA has the information that allows the cell to then produce an RNA, where this information is stored in a way that the cell can understand and then produces the protein that it needs. This is true, but it's not exactly accurate, because this RNA production part is actually two pieces. When the DNA is transformed into RNA, the RNA is composed of exans and introns. Exans are the information that the cell needs to produce the protein. Introns are pieces of information that are not important for the sequence of the protein. So the cell can recognize what is an intron, what is an intron and what is an exan. She removes what is not necessary, the introns, puts the exans together to form the correct message that the cell needs to be able to read to produce the protein. This system of removing the not important parts and putting together the important ones is called splicing. So, as the name says, if you have a splicing mistake, then you are not able to do splicing. How does this look like in Mila? So you have the DNA where you have a small mutation. This mutation, when you move it into RNA, it's within the intron and the exans. This mistake here confuses the cell, and the cell can no longer distinguish what is an intron and what is an exan, what is important for the production of the protein and what is not. So when it tries to remove the introns, it cannot remove this one. So in the end, this message does not make sense, so it cannot produce the protein. Now, in the good fortune of Mila, in a way, we know how to fix splicing mistakes. Using a splicing therapy where we use very small pieces of DNA that are called anti-sense oligonucleotides. It's a horrible word for something very simple. It just attaches itself to the mistake and hides the mistake. So the cell can no longer see where the problem is, and it can yet identify that this is an intron and this is an exan, produces the right message, and then it can produce the protein. Sounds quite simple, right? So taking this approach of these anti-sense oligonucleotides, doctors and scientists collaborated to actually produce Mila's drug in one year. Please bear in mind that a normal drug, until it goes to clinical trials, can take at least 15 years. So one year is quite the achievement. How did they do this? In the lab, they started by producing several different versions of this anti-sense oligonucleotide, this small piece of DNA, that could possibly work to fix the mistake, to hide the mistake. Then they tested them in Mila cells, and out of all of them that they tried, they found the one that works best, and they'd call it Milacin, in honor of Mila. Then, just because you can hide the mistake, does not mean that the protein is doing its job. So how did they check for this? They went again to Mila cells, and here you have the normal cells of Mila that produce these dense, black structures in the cells. When they treated it with a drug, these structures disappear. So this tells you that this Milacin, this oligonucleotide, can hide the mistake enough, that the cell can produce a protein that can do its job, that is remove the waste from the cell. Also, they needed to test this drug in animals to prove that this drug was not toxic. So with all of these, they could go to the clinical trial organization, and they finally got approval to start a clinical trial in 2018, January. Again, this drug is made specifically for Mila, so it's a clinical trial for Mila. So there's only one person in this clinical trial. So they started by giving small doses of this drug to Mila, just to figure out if she's getting a bad reaction or if she's getting any side effects. To give this drug, you need to give it within the spine. What you do is you inject the drug between the vertebra of your spine, in the liquid that surrounds the spinal cord. This liquid that surrounds the spinal cord will then transport the drug through the brain and the spine, so through the nervous system of Mila. And there you can reach the cells and do its job. Now the drug did not produce any side effects that they could see, and it was not toxic for Mila, so now that they know that it's good, now they only need to give a maintenance dose every three months. So in this way, Mila cells always have enough of the drug to keep on working. Now the big question, did it work? The report about this treatment and about the clinical trial came out in October of this year, so it's fresh out of the press. And according to Mila's mom, Mila does not slump, she can sit straight, and her arms and legs are not spastic, so she does not have muscle contractions. This means that this drug has improved Mila's quality of life. I know that sitting straight does not sound like a big achievement, but it does mean a lot for someone to be able to sit so that he can get a food, not to be strapped into a chair, for example. Also, another gigantic improvement on Mila is that the number of her seizures and the duration of these seizures decreased by 50%. So by the time that she started the treatment she was six years old, she was having 30 seizures a day. She only had now at the end of the treatment 15 seizures a day. From almost two minutes per seizure she was reduced to only a few seconds, so this is huge. On the other hand, her communication skills, social skills and her motor skills did not improve that much. Also, the size of her brain continued to decrease. This is not so surprising because this is a treatment, it's not a cure. It's there to help the cells that are already there. It cannot, if the cells have already died, it cannot create cells out of nowhere. So it's helping the cells that are there, but if she already lost them, then there's nothing we can do about this. What is the future of Mila? Well, it's hard to say. As I said, this report came in October, so after almost two years of treatment. So, and this is the first clinical trial. She is the only person that can receive this drug. So it's not like we have anything to compare it to. So we don't really know what's going to happen. Oh, the only thing we can do is wait for the doctors to continue to understand and follow up the development of Mila and see how she is responding to the drug and how she is developing in the future. There's no guarantees. So, Mila was the first person to receive a personalized drug treatment. So it's official now. Personalized medicine is a reality right now. What does Mila's story actually mean for the future of personalized medicine? So Mila's drug can only be used by her. So it's not like I can take this drug and give it to someone else. But the idea on how to build this drug, how to go through the clinical trial approval phase and how to give the drug, all of this can be adapted to the next person. And there is about 1.3 million people that could benefit from a treatment like Mila. So this is a lot of people. Also, I do have to say that producing a drug in a year is quite the achievement and it's not likely to happen again. The truth is that they made it in a year because there was a lot of scientists and doctors that just came together, dropped everything, gave their money and their time to produce this drug in a year because Mila was in already a very severe state. But also Mila was lucky because we already knew some things about splice therapies. We already had some ideas on how we could fix the issue. So there's about 30 years of research that are in that one year of production. And some other gene diseases might not be that lucky. Also, medicine, personalized medicine, so medicine for one person is also risky and costly. It's risky because you can only test this drug in an animal and in the person that will receive the drug. This drug is made for that one person. I cannot test it somewhere else. So it's impossible to predict if it's going to help, if it's going to be worse. What is the outcome? So in the end, personalized medicine is a reality. Mila is a success story because independently of how far she has come and even if some of her treatment has not given the fantastic results that we were expecting, still her parents keep on saying that battens is really bad. But in her mother's opinion, battens, for her, it looks like battens has stopped. So she took the risk and it paid off. And it's up to every patient and to the family of the patient to decide if they also want to take the risk. And thank you. Lily, thank you for your splendid talk. Now we will have five minutes for your questions to Lily. So raise your hands if you're interested in anything you might want to ask her. You can wait for the microphone. Microphones for everyone. Nice. Which country was this done in? So it was done in the US. And they paid for that. So Mila's mother, when she was diagnosed with the disease, she started a foundation. It's called Stop Battens Foundation. And with this foundation, she collected some money. Also, so actually the cost of this was not made public. So we don't know how much it cost. But we do know that the mother was collecting money. We also know that many of the researchers gave some of their own grant money to do some of the research that was involved in here. So I cannot tell you how much it cost. But it's not like you're going to get a big revenue like in big pharma, right? Any other inquisitive guests? The Mr. on the third row. Okay, thanks. So just to make sure I understood, this was the first case of personalized medicine in documented history? Or were there some other case? It's considered the first case of personalized medicine because it's the only one that is documented. But there are already some after this trial, there are already at least three other trials that are rumored to be happening right now for other types of diseases. But we will know more when they come out in the future, which I don't know when. So and this was also the first documented case of this type of disease with all these genes combinations or were there also before? So buttons disease was known before, as I said, that are 14 types of buttons and each of these 14 types is unique enough to require their own clinical trial. And there are some types that are slightly more common. So then these have been a bit more research and there are some types that have basically no research at all. On the other hand, the type of millers where she has the known buttons mutation from the father and this splicing mistake, this is completely unheard of. That they know no one else has this. She's the one in a million. Okay, thanks. Thank you. We will have time for one last question. I think I saw one raised hand over there. Don't look around, it was you. Don't be ashamed, go ahead. So if they would have sequenced her, both the copies of her DNA when she was born, would they have known that this was there before as soon? And if yes, then would it make sense to sequence both copies of DNA for every child that is born just to see if there is a mistake? Lily, could you please repeat the question? This is actually a great question because it's a big debate right now. So he asked me, so by the time that we gave the treatment to Mila, it was already too late because she had already lost a lot. She could already not speak so well and not move so well. What if they had found out the problem when she was born, then what would have been the outcome? So theoretically, if they had found out when she was born, when her cells were not, there were not that many dead cells, then her outcome would have been a normal child. Theoretically, right? If the treatment goes perfect, there's nothing wrong with it. We are giving the right dose at the right time. Like if you find out in the beginning, then she will be a normal child. And then he asked me, so then should we just scan the entire genome of every child when they are born to then figure out if we can prevent some of these diseases? This is actually something that Mila's mother is actually claiming or she's suggesting that maybe now that genome sequencing, so sequencing our genome is cheap, why don't we just do it to find out if a child has a severe condition that can be treated from the beginning before it's too late. The thing is that this is an ethical debate because if you are sequencing the entire genome, then you're also going to know every single thing that genomically can happen to that child. Is he prone to heart conditions? Is he going to be tall? Is he going to be short? So all of these things. And the question is, do you really want to know that far? Is it really worth it from the 20,000 children that will be better to the other 2.2 million and the price that it costs? It's a great question and a great answer too. Don't forget to look for Lily in the break and don't be ashamed to ask her any further things you might want to ask. Yes sir. Thank you Lily, thank you for your splendid talk. Thank you.