A dying child, a mother’s love and the drug that changed medicine

Hundreds of thousands of children are born each year with fatal neurodegenerative diseases. A gene therapy breakthrough offers hope of not just a treatment, but a cure
A dying child a mothers love and the drug that changed medicine
Getty Images / WIRED

Mila Makovec loved the great outdoors. Born in November 2010, she grew up on the outskirts of Boulder, Colorado and was skiing by the age of two. Before her third birthday Mila would go on long hikes, preferring to make her own way rather than be carried in a baby backpack. Shortly after her third birthday Mila started rock-climbing. “This is not just a mom boasting about her child,” says her mother, Julia Vitarello. “She was really outgoing and advanced. But then,” she adds, “I started noticing things.”

Before she turned four, Mila had started walking with an inturned foot. At the doctor’s surgery there was little alarm. Mila was diagnosed with tibial torsion – an inward twisting of the shin bones that is relatively common among toddlers. But, for Julia, the diagnosis didn’t add up. Over the coming months Mila became clumsier and clumsier. She would stumble and fall; her speech, previously eloquent and exuberant, became slow and staccato. In 2015, by the time Mila was five, doctors started using the word ‘delay’ – suggesting that she had been born with something that was hindering her development. “That didn’t make sense,” says Julia. “Mila was advanced.”

The hunt for a diagnosis was arduous, encompassing more than 100 visits to doctors and therapists. Many doctors who assessed Mila commented on how developmentally advanced she was, despite her ever-growing list of symptoms. Then came the suggestion that maybe, just maybe, she had something incredibly rare. Julia started carrying around a piece of paper to note down any symptoms of a potential neurological condition. “First it was stepping on toys and breaking them. All the toys in our house were broken. I would ask her, ‘Mila, what’s that in the corner?’ and she would say, ‘Oh, it’s a butterfly.’ The next day I would ask again and she would look away like she didn’t know.” Suspecting that Mila might have a vision problem, Julia took her to an ophthalmologist and an optometrist, both of whom said she seemed fine. “They also told me to chill out,” Julia says.

One day in December 2016 Julia decided she needed some air. She went for a run, got bitten by two dogs and barely flinched. “I didn’t even realise – I’d been crying the whole time for Mila.” Perceiving that she could no longer cope, she packed up a duffel bag, put Mila in the car and drove her to the Emergency Room. “I heard the word ‘seizure’. I heard the word ‘blind’. She couldn’t even stand,” Julia says. Mila spent a week in hospital and received a myriad of tests. “I saw her decline so quickly. Everything changed that week.” Mila was diagnosed with Batten disease, an incredibly rare genetic disorder that gets progressively worse and is always fatal. “I felt enormous relief,” says Julia. “And I also felt very guilty. I’d been told I was crazy for three years, but there it was, in her genetic code.”

Children with Batten disease have a problem with their lysosomes, enzyme-filled bags within cells that clear waste molecules. With defective lysosomes, this waste builds up and kills cells, causing brain damage and, by adolescence, death. Symptoms normally appear between the ages of five and ten years. Children suffer from vision problems and seizures. Their behaviour changes, they become clumsy, their spine starts to curve. The disease is fatal and there is no treatment or cure.

Mila’s doctors in Colorado sequenced the protein-coding part of her genome and found an error in one copy of a gene called CLN7, which codes for a protein that it is thought help molecules move across the membrane of the lysosome bags. To have Batten disease, both copies of CLN7 – one from the mother and one from the father – need to have mutated. Mila’s doctors could only find a defective gene from Mila’s father. To find the other mutation, Mila’s whole genome would need sequencing. At the time few labs in the world – let alone just in the United States – could do this, and even then it was prohibitively expensive and time-consuming. Mila was already six years old and her condition was worsening by the day.

But something else was at stake. Azlan, Mila’s younger brother, could also have been carrying the same fatal mutations. If he did, then he would soon start to show the same symptoms. “I would look at my son, who was totally normal, just like Mila was, and the pain drove me to try and figure out what the mutation was,” Julia says. Without knowing what both mutations were, there was no point checking out her son. To answer that question – and confirm Mila’s diagnosis – someone, somewhere, would need to find both mutations.

Faced with such challenges, many parents look to the frontiers of medicine. Julia founded a charity in her daughter’s name, Mila’s Miracle Foundation, and set herself a fundraising target of $4 million to put towards scientific research and treatment. Her end-goal was gene therapy. Gains made in this field are slow and expensive, but the need for breakthroughs is acute. Every year 7.9 million children are born worldwide with a serious birth defect of genetic, or partially genetic, origin. That’s six per cent of all births. An estimated 3.3 million of those children will die before they reach their fifth birthday. Treatments for such diseases are scarce, and cures are almost non-existent. To raise money for research, Julia realised she needed to improve awareness of Batten disease and other similar fatal genetic diseases. “I learned that my tool was telling Mila’s story,” she says. “So I started telling it to everyone. I let the press into my house, I went on the news. I hated it – I was so sad. But it was the only thing I could do.”

In January 2017 Julia got a phone call from a doctor named Timothy Yu, a neurologist and neurogeneticist at Boston Children’s Hospital, whose work just happened to involve sequencing the genomes of people with autism. He had read about Mila on Facebook and wondered if he could help. Yu has run a lab at Boston Children’s Hospital since 2000 and has been carrying out whole-genome sequencing since 2010. “We were one of the first to apply it to human disease,” says Yu. Not only did he think he could help Mila and her family, but the work also aligned perfectly with his academic interests. This gave Yu both the will and, critically, the means to track down the missing mutation. “My lab has been figuring out how to use high-throughput sequencing to diagnose disease and discover new causes of disease for a long time,” he says. “We know that there are a lot of cases out there of genetic conditions that go undiagnosed because traditional clinical testing doesn’t cut it.”

Yu’s task was to find a fragment of a needle hidden in the haystack of Mila’s genetic code. The doctors in Colorado had found the mutation from Mila’s father, meaning that Yu and his team could focus their efforts on finding the one inherited from Julia. “At first we struck out,” he recalls. “All the standard ways of looking at the human genome sequence gave us nothing.” After two days of failure, Yu and his team took a different approach: they started painstakingly combing through the raw genetic data by hand.

The human genome is three billion base pairs long. To analyse it manually, Yu and his team split it up into chunks that are about 100 letters long and started looking for the one tiny anomaly that would confirm Mila’s diagnosis. After days of searching, Yu’s team found something. A section within the CLN7 gene inherited from Mila’s mother didn’t match up properly with the sequence of a normal CLN7 gene. Later analysis would reveal that a 2,000-letter stretch of DNA had ‘jumped’ and landed there, breaking the gene. This extra chunk of DNA caused an error in Mila’s cells, disrupting their ability to make protein. This, in turn, had broken her body’s ability to clear out waste molecules. When he called Julia to deliver the news, Yu also had another crucial piece of information to share: while Mila had inherited the mutations from both her mother and father, Azlan had inherited neither. “That was an enormous, enormous relief,” says Julia. “But also a huge reminder that Mila was going to die.”

Yu’s initial promise to Julia was to find the mutation, and nothing more. But her jumping gene was unusual. It had essentially landed on a part of the gene between the important parts that encode the instructions for making the crucial cell-cleaning protein. Mila’s mutation was, it turned out, merely changing the way the instructions were assembled. Most mutations destroy the instructions. In Mila’s case, they were disrupted but still intact.

Just as the stars had aligned to connect Mila with Yu, so they aligned again when Yu and his team started to research possible treatments. In December 2016 – only weeks before Yu first spoke to Julia – the Food and Drug Administration (FDA), the US federal agency responsible for drug regulation, had approved a drug called spinraza. The drug is used to treat spinal muscular atrophy, a rare neuromuscular disorder that causes muscle weakness and is a leading genetic cause of death in infants, many of whom die before the age of two. The defect that spinraza targets is the assembly of a critical gene called SMN2. Spinraza reassembles this gene by removing the defect. This type of drug is called an antisense oligonucleotide (ASO) and it works by binding to defective RNA, hiding it and tricking cells into producing a normal protein. Yu had an idea: could he create a similar kind of genetic plaster to cover Mila’s fatal defect?

“People were talking about it being curative,” says Yu. “I went into neurology because there is a huge unmet need. But, in reality, there are very few curative therapies in neurology.” Spinraza changed that. “When we looked at what spinraza did for those kids and we looked at the mutation that we found in our patient, it was the same story. Why couldn’t we pull the same trick?” It was a huge undertaking, made all the more challenging by the fact that Yu and his colleagues had never made a drug before. “We’re an academic lab. I’m a clinician, I’m not a drug developer. But when I looked at the basic science I couldn’t see a reason why this wouldn’t work.”

Between April and October 2017, Yu and his team created a scientific proof of principle – a new drug, targeted at one tiny mutation in one patient. If it worked, it would become the first single-patient drug ever created. But they faced one additional, potentially insurmountable hurdle: the FDA. “We weren’t looking to commercialise a drug,” says Yu. “We weren’t looking to do what a pharma company would do. What we wanted to do was apply for permission to treat our patient under emergency access.” This regulatory route allows doctors caring for individual patients to, for example, apply to use a drug that has been approved for use on another disease or a drug that is still in development and has not yet gone through clinical trials. If the need is dire – and the application is successful – then the treatment can be used. “So we decided to choose that path,” says Yu. “Except that path had never been undertaken for a drug that hadn’t undergone some professional development before.”

Yu found himself at the frontier of not just medical science, but also regulation. The drug that he and his team had conceived had been developed in an academic lab, not by a pharmaceutical company. Not sure where to start, Yu naively called up an FDA hotline. “There’s a 1–800 number you can call. So I called them up and told them what I wanted to do.” The FDA agreed to set up a conference call, which Yu ended up taking while on holiday. Sitting on the patio of a house that he and his family had rented for the weekend, Yu addressed the 15-member FDA panel. “It was after this conference call that I realised, ‘Oh gosh, I think it might be good to get some additional advisers on our side.’”

All the while Mila’s condition was worsening. One day in the summer of 2017, around six months after the diagnosis, Julia was lying in bed with her daughter. It was dark and Mila, as had become common, was struggling to get her words out. “Her sentences were getting shorter and shorter. She was saying, ‘Mommy, Mommy’ and she just kept getting stuck on ‘Mommy’. She could never get the rest of the sentence out. She was driving me nuts,” Julia says. “But then I realised I might never hear her say Mommy again. And that happened. I took a video that night in the dark. And I heard her say ‘Mommy’ and it was just horrible. It was really horrible.” By the autumn of 2017 Mila could no longer speak. All her food had to be blended to the consistency of mashed potato, and even then she choked all the time. She had also been fitted with a gastrostomy tube, in preparation for the day when she would no longer be able to eat or drink.

Back in Boston, Yu and his team were grappling with two challenges: how could they prove their drug was safe to use, and how could they manufacture it quickly enough? To tackle the first challenge, Yu’s laboratory tested the drug they had developed on skin and blood samples they had taken from Mila. This process, Yu recalls, was simple enough. But the logistical challenges proved more complex. The drug Yu had created, like spinraza, is known as an antisense oligonucleotide. For a laboratory-grade version of this drug, Yu would expect to pay as little as $10 for a small sample. For a higher quantity, maybe $300. But clinical-grade manufacturing is more costly and complex. Yu started calling around and was told that it would take six to nine months and cost hundreds of thousands of dollars to manufacture a clinical-grade version of his drug. The laboratory-grade version could be turned around in a week. The manufacturers he contacted were also only really geared up to produce huge quantities, perhaps as much as half a kilo. Yu only needed 20–30 grams. Eventually they found a company willing to manufacture the drug in the right quantity and for the right price. The negotiations with the FDA were complex, but, remarkably, Yu continued to make good progress. But time was slipping away and so, in October 2017, manufacturing of the drug began, without FDA approval.

By this point Mila was having up to 30 seizures a day. “She was smashing her legs and arms against tables. She was bruised. She was going down very quickly,” says Julia. Mila’s disease, as is typical for Batten, was manifesting as a series of plateaus and cliffs – for weeks Mila’s condition would stabilise, then she would rapidly deteriorate, before stabilising again. Each fall took another chunk of Mila with it. In January 2018, days after Julia and Mila had arrived in Boston hoping that FDA approval was imminent, the good news arrived. “I was so overwhelmed,” Julia says. Yu assembled his team and asked Julia and Mila to come into Boston Children’s Hospital. They were taken to an unremarkable back room, in which sat a refrigerator packed with vials of the new drug. The drug – the first of its kind ever developed for just one patient – now had a name: milasen. Before she received the first dose, Mila’s doctors anaesthetised her and carried out one final MRI scan of her brain and spine. Once the scans were done, she was wheeled into the room next door to receive her first dose of milasen, administered via a lumbar puncture.

For Julia and Yu it was the first moment of pause for almost a year. They sat in the MRI waiting room, leaning forward, their elbows on their knees, and they paused. “I’d been working day and night for the previous year – it was probably one of the most intense professional periods that I’d encountered,” says Yu. “In the weeks before, people had come up to me saying I was going to lose my licence for this. This is a very risky thing to do. But there was no other help coming. It was very, very clear that if we didn’t do anything, she would have no quality of life and she would die within a few short years. I really came to peace with it, professionally and ethically and clinically. So we definitely did pause and take a deep breath and reflect on where we were.”

The day after was blissfully boring. Mila had no adverse reaction to the drug. The first few doses also went without a snag and, over the next six months, Mila’s condition started not just to stabilise, but to improve. The number of seizures she had went down drastically and also became less severe. Where before they had been long and violent, now they were short and calm. Mila also began to hold up her own body again and started eating. She even started walking. With her mother standing behind her, their arms interlocked, Mila was able to take a few, stumbling steps. “It was a pretty big deal,” Julia says.

As the days turned to months, and the months to years, Mila’s disease started progressing again – though more slowly than it had before. “We know it’s not all a fairy-tale story,” says Yu. “We believe this drug is definitely helping, but there are areas in which this disease has progressed that are meaningful and impactful and sad. But I think it has provided her with an improved quality of life.”

Julia agrees. “Mila has always been a kid who loves imagery and storytelling and songs and has reacted well to nature. I try my best to engage her mind and body.” Most days, a girl the same age as Mila comes round to read her stories. “If she touches Mila’s hands, she feels a child’s hands,” Julia says. When Mila’s brother Azlan runs around the house and screams and shouts, Mila hears a child’s voice. “I believe, as her mother, that she’s absolutely listening and paying attention.”

Mila’s story is about so much more than simply one patient. “It’s extremely important to me that all the blood, sweat and tears that we put into milasen is not just for Mila,” says Julia. “It’s opened the eyes of everyone. It’s shown what’s possible.” The story of Mila represents the most profound realisation of personalised medicine yet. Her legacy, it is hoped, will be to make the path to treatment easier and less expensive for the next patient in desperate need. “We can imagine a situation where the tools for drug development are good enough, and accessible enough, that a scientist can apply them to a single patient,” says Yu. In this respect, Mila’s story is a story from the future. The pharmaceutical industry has already progressed from developing drugs to treat diabetes and heart disease – illnesses that affect millions of people – to develop treatments like spinraza, which target diseases found in only a few thousand patients. Milasen has shown that scientists have the tools at their disposal to develop treatments that can be applied to only one patient with a specific, targetable genetic mutation.

“There’s a lot more work to do to be able to prove that the work we did with milasen, as a proof of principle, can be scaled,” Yu says. Now, with an example of how it can work, he believes that healthcare is on the brink of a major change. Antisense oligonucleotides – the genetic plasters behind the success of milasen and spinraza – will likely be the first wave of this change. “These are incredibly easy to make. You make them out of a machine that’s about the size of a large, soft-serve ice-cream machine,” says Yu. “You type in the sequence, add in the ingredients and the drug is synthesised and comes out twenty-four hours later.” This, says Yu, is a field that can become cheaper and more efficient in a relatively short space of time.

But, as he found while developing milasen, two major hurdles stand in the way: a scientific hurdle and a logistical one. “I’m a scientist, right? And we’ve still only done an N of one,” Yu says, using the scientific term for a clinical trial with just one patient. “If a graduate student comes up to me and shows me an experiment with an N of one, I tell them to go back and do it at least three more times. So conceptually, that’s what we need to do.” On the logistical side, Yu realises there are more complex challenges to overcome. “In order to scale, this process has to be made simpler and less expensive,” he says. More than 70 people were involved in the development of milasen. The cost of the development has never been disclosed, but spinraza, the treatment for spinal muscular atrophy that inspired Yu to develop milasen, costs $750,000 in its first year and $375,000 annually thereafter, placing it among the most expensive drugs in the world.

To be available to the hundreds of thousands of children born with fatal neurodegenerative diseases that can be targeted by antisense oligonucleotides, the price of treatment needs to come down, right down – and fast. For that to happen, drug manufacturers will need to develop processes and business models that enable them to make lots of drugs in very small batches with quick turnaround times. Think going from spending nine months developing one drug to spending one month developing nine drugs. Regulators will also need to introduce new pathways for targeted, small-scale treatments. This will be a huge challenge for an industry that is used to regulating, manufacturing and monetising treatments that can be taken by hundreds of thousands or millions of patients, rather than simply a handful. Or one. Milasen shows that it can be done once, and so Julia and Yu are now focusing their efforts on showing it can be done time and time again.

In the future, the mutations that cause rare, often-fatal diseases could be targeted with precision medicines just like milasen. As whole-genome sequencing costs come down, such checks will become more routine – giving physicians access to all the data they need to make an early and accurate diagnosis. Yu sees a future where parents of children with potentially fatal genetic mutations are immediately connected to experts who can explore the feasibility of making a drug and start the process in days, not months.

Parents could even be screened before they try for a child, to find out if they have mutations that could cause a fatal or life-limiting disease. “They can know that they have a one-in-four chance of having a child with this disease,” says Yu. The parents would then receive counselling to help them make the best decision. A foetus with an incurable, fatal genetic mutation could be aborted. Or, if in utero procedures could correct the genetic fault, treatment could be carried out at the earliest opportunity to give the child the best chance of a long, healthy life. The potential to eradicate some fatal genetic diseases before they even exist is one of the great promises of precision medicine. “The diagnostic portion is ready to implement right now,” says Yu. “We just need the political will and the money to do it.”

Julia compares the situation she faced when Mila was diagnosed with Batten to being handed an empty toolbox. Now, that box contains one truly remarkable tool. If – and it’s a big if – another child has Batten caused by the exact same genetic mutation as Mila, then there is a fridge in Boston that contains a lifetime’s worth of treatment. And if that child is diagnosed sooner than Mila, then there’s a chance they could press Pause on the disease and slow its progress earlier – perhaps before that child even displays any symptoms. “As a clinician and as a human, I think about that all the time,” says Yu. “What if we could have gotten to Mila sooner? What if we’d been able to make this diagnosis in Mila at age four? We only met her at age six.” Batten is a disease that gains momentum – cells in the brain start dying, symptoms compile and accelerate. “Coupling this kind of approach with earlier diagnosis is just so critical,” says Yu.

“No one wants to hear the story of a dying child,” says Julia. “But when it’s told in the light of hope, people want to listen.”

Mila Makovec passed away on February 11, 2021.

James Temperton is WIRED's digital editor. He tweets from @jtemperton

Adapted fromThe Future of Medicine: How We Will Enjoy Longer, Healthier Livesby James Temperton. Find out more and order your copy of the book.