Saving Mila: How a tailor-made therapy, developed in a flash, may have halted a young girl’s rare disease

As 6-year-old Mila’s favorite movie, “Frozen,” played, her father held a newspaper up in front of her face. She was rapt — her favorite song was on — but she didn’t even flinch.

That’s the moment Mila’s parents realized that she had gone completely blind. And they finally knew, now, after months of concern and sinking suspicion, that something was dangerously wrong with their bright, engaging daughter.

Mila has Batten disease, an ultra-rare, neurodegenerative genetic disorder. For every child diagnosed, the prognosis has been tragic: Batten is always fatal.

But Mila’s parents, Julia Vitarello and Alek Makovec, now have a glimmer of real hope. Thanks to a remarkable effort on the part of scientists, regulators, and Mila’s family, an experimental therapy — developed in record time — could very well be halting her disease in its tracks.

Drug development typically takes several years before a new therapy can even make it into clinical trials. Mila, however, made it from diagnosis to bespoke therapy in just over a year. Her case serves as a proof-of-concept in efforts to rapidly develop and deliver precision medicine — as tailored to a single patient. The drug was designed specifically for Mila’s unique mutation, and it’s not clear whether many more children carry it as well, or will benefit from the therapy.

“In a way, this is more like a bone marrow transplant or a surgery than a pill,” said Dr. Timothy Yu, the Boston Children’s neurologist who was largely responsible for bringing Mila’s therapy to fruition.

But now, nine months into her unique treatment, Mila’s parents — and physicians — are hopeful.

“Batten is really cruel, and she lost a lot before she began therapy,” Vitarello said. “But to me it seems her disease has absolutely stopped.”

Mila was always an extremely advanced child. Growing up in Colorado, she was skiing by 2 ½, loved biking and hiking, and was a complete chatterbox.

But at age 3, Vitarello began noticing subtle things about her daughter that concerned her. At first, Mila’s foot started turning inward. Then at age 4, people would remark that Mila — who had always been so coordinated — was a clumsy little girl. By 5, however, things were becoming more obvious. One guess was autism, but Vitarello knew that wasn’t quite right, given how rapidly her talkative, adventurous daughter had regressed. When Mila’s blindness became apparent, the search for an answer kicked into high gear.

After shuffling from neurologist to neurologist, Mila received clinical genetic testing, which revealed she carried one mutation that leads to Batten. And she showed all the hallmark symptoms of the disease. In late 2016, the diagnosis was made.

“I felt an incredible sense of joy and relief, which might sound strange, but it’s the truth,” Vitarello said. “This confirmed that I wasn’t dreaming, that I wasn’t crazy — at least I knew what this was.”

It was also horrible.

Batten disease has a very specific trajectory, and it’s always devastating. It’s part of a family of diseases called lysosomal storage disorders — in which a genetic defect leads to a deficiency of an important metabolic enzyme. This, in turn, leads to a toxic buildup of proteins and lipids in the brain — and those affected end up with degenerative disease.

There are more than a dozen different variants of Batten disease, caused by miscoding in slightly different genes, but as Vitarello describes it, the illness combines symptoms of Parkinson’s disease, dementia, and epilepsy, with blindness added in. There’s some work being done in therapeutics for Batten — the Food and Drug Administration last year approved an enzyme replacement drug, Brineura, to treat one form of the disease. But there’s nothing available for Mila’s gene variant, which is called CLN7.

“When I was first learning about Batten, I saw MRIs with empty brains. Children lifted with mechanical lifts out of their beds, who were previously laughing and playing and going to school,” Vitrarello said.

Her way of coping with her daughter’s devastating prognosis was research, and activism. She launched her own philanthropy — Mila’s Miracle Foundation to Stop Batten — and used her skills as an advertising and marketing professional to raise awareness and funds for further study. With the help of crowdfunding site GoFundMe and other sources, Vitarello raised nearly than $3 million — with aims, initially, to fund a gene therapy for her daughter’s variant of the disease.

She also reached out to anyone who might be able to help. That, ultimately, led her to the doctor who would change her daughter’s odds for survival: Yu, a neurologist who researched pediatric genetics at Boston Children’s Hospital.

Mila’s parents knew that she carried one copy of the CLN7 gene from her father. But they wanted a full molecular diagnosis: They still didn’t know what DNA her mother had contributed — and Batten, as a recessive illness, would only manifest if a person carried two copies of the diseased gene. If they were going to go down the gene therapy route, they needed a complete understanding of Mila’s disease.

So Vitarello put out a plea on Facebook, back in January 2017, saying that she needed someone to pore through Mila’s entire genome in search of the missing variant, and to do it quickly. Her post made its way to a Facebook group of physician mothers — and was forwarded along until it found its way to Yu.

Yu got in touch with Vitarello, and offered to do whole-genome sequencing for Mila at Boston Children’s. A month later, Yu had found the other copy of the Batten gene.

He also had an idea.

The mutation Mila had inherited from Vitarello was intriguing — it’s a called a retrotransposon, which in this case was a 2,000-letter stretch of code that moved from one portion of the genome into her CLN7 gene and inserted itself there, altering it. As a result, the protein that this gene was supposed to help manufacture was shortened and ineffective. But the necessary DNA coding was still there — unchanged — to make the right enzymes in Mila’s body. It just was being overshadowed by the retrotransposon, an interloper.

Around this time, a new drug called Spinraza had just been approved by the FDA. It treats a genetic illness called spinal muscular atrophy, and has dramatically improved the lives of children with that debilitating condition. It works by binding to faulty RNA that’s produced by the mutant DNA — allowing the correct portion of RNA to manufacture a functional enzyme. The drug, called an antisense oligonucleotide, worked in the exact way that might have been able to help Mila — if Yu was able to engineer a drug that could bind to her own unique mutation.

And that’s exactly what he suggested to Mila’s parents.

Yu began looking for a way to synthesize his own oligonucleotide drug. They studied just about every paper linked to Spinraza’s development, and carefully mapped out the intricacies of why Mila’s genes were behaving as they were. They worked closely with FDA regulators. They made a lot of phone calls. They talked to anyone who would listen.

“This was an aggressive timeline — perhaps the most aggressive attempt at trying to bring a drug into a human that we’ve seen,” Yu said.

The drug was designed by August that year, and scientists began testing it in Mila’s cultured cells. From there, Yu began rallying dozens of scientists who might be able to help with manufacturing, toxicology, and advanced testing. This included members of Boston Children’s experimental therapeutics unit, and others in neurology, genetics, and anesthesia experienced in administering Spinraza.

Yu’s team sped through regulatory hurdles, under the FDA’s compassionate use pathway, and a single patient clinical trial was greenlighted by the winter. A contract manufacturer created doses of the drug to administer to Mila. It was named, fittingly, “milasen.”

Things had taken a turn for the worse for Mila by November, though. She’d been experiencing seizures for months, but suddenly she was having around 30 every day. Her legs were giving out while she walked; she would choke as she ate food that had already been pureed. Things Mila found funny no longer made her laugh.

So Mila’s family began the clinical trial in earnest — despite the fact that milasen had barely been evaluated in animals, and its efficacy was largely unknown. But as long as the drug didn’t cause Mila excruciating pain every day, the answer was simple.

“There was no other option,” Vitarello said.

Mila began taking milasen in January this year. It’s administered through an IV in her spine, and is meant to be given once every three months. Yu began dosing her cautiously, escalating the amount she was given as it became apparent she could tolerate the treatment.

And it seems to be helping.

“I’ve seen quite a lot of improvements,” Vitarello said. “To other people they may be small, but to me, they’re huge.”

Whereas Mila once had 30 seizures per day, lasting about two minutes each, she now seizes about five to 12 times a day, and only for a couple of seconds.

“The rule with Batten is that the seizures are supposed to get monotonically worse and worse,” Yu said. “Instead, they’re becoming less intense.”

She doesn’t slump, but sits upright. Her arms and legs aren’t as spastic. And, most importantly, Mila is more alert. She’s listening carefully when she’s spoken to, and laughs when things are funny. She’s aware of the world around her.

“She’s just here, now. She’s present,” Vitarello said.

It’s still early, and Yu cautions that his team will understand more about Mila’s progress in the coming months. It’s tough, on a molecular level, to measure how the drug works — the cells most affected by the lethal protein buildup are in the brain.

Because Mila’s specific mutation is so rare, it’s unlikely milasen can be used on its own to treat other children with Batten. There’s a chance, however, it may help others who carry the same retrotransposon somewhere in their genome, so Yu’s team examined another 500 full genomes, just to see if a similar retrotransposon would pop up anywhere. So far, they’ve been unable to find one.

Still, Yu’s team, and Vitarello, hope that drug development might be similarly fast-tracked for other diseases, and other children.

“Right now, we’re bushwhacking through the trees, because there is no clear path,” Vitarello said. “But Mila’s story, I hope, is breaking some ice — so that something similar could happen for other children with a lot of different diseases. There’s no reason it can’t — one step at a time.”

Tamar Grossman, director of translational medicine at Ionis Pharmaceuticals, is less hopeful. Her company developed Spinraza, and she said during a public conversation at last week’s American Society of Human Genetics conference in San Diego that the breakneck pace at which milasen was developed will be hard to replicate.

“The uniqueness of this program is N of 1: It’s one patient, one disease — a unique situation,” Grossman said.

As soon as you have more than one patient, she said, the FDA requires a placebo-controlled trial, and a natural history trial — tracking patients who might have a predisposition for developing the disease, she said.

“I’m sorry to disappoint,” she said. “But it can’t happen next week.”

There’s also the matter of cost. Although Yu declined to say how much Mila’s treatment cost, funding came from the Batten foundation, Boston Children’s, and Yu’s own research funds.

Vitarello acknowledged the “stars did align for Mila’s treatment.” A sick girl’s proactive family found a physician who had the ingenuity — and funding — to take a deep dive into her condition. A groundbreaking new drug, Spinraza, had just months prior been approved — and served as inspiration, and a template, for Yu’s team to follow.

“It’s amazing, and inspirational, but it has a context,” said Jannine DeMars Cody, founder and president of the Chromosome 18 Registry & Research Society and a professor at University of Texas Health Science Center at San Antonio. “It’s 30 years of parents and scientists working to create the context so something like this could happen so quickly.”

An earlier version of this story incorrectly described the amount of money Vitarello raised. It also incorrectly described the precise target of milasen.