Sitting in a freezer at Boston Children’s Hospital is a drug you won’t find anywhere else. It’s called milasen, and the 18 g that the hospital custom-ordered nearly 2 years ago should last for decades. That’s because milasen was designed to treat a single patient—a now 8-year-old girl named Mila Makovec.
Milasen was built on decades of work on a class of drugs called antisense oligonucleotides. But after Boston Children’s Hospital scientist Timothy Yu diagnosed Mila with a never-before-seen genetic mutation, he took only 10 months to go from idea to injection. It’s a record-shattering sprint in the typical drug-development marathon, and an unprecedented degree of personalization for a chemical drug.
This month, Yu finally published details of how his lab went from diagnosis to treatment at lightning speed (N. Engl. J. Med. 2019, DOI: 10.1056/NEJMoa1813279). While the story of milasen could be seen as a template for other highly personalized drugs—what the field has come to call n-of-1 therapies—it also raises questions: Who should get these treatments? How will they be funded? And how will the US Food and Drug Administration regulate these projects?
When Yu first heard about Mila, he had no intention of launching a drug-development effort. In fact, he had never designed a drug or even worked with antisense oligonucleotides before.
Yu runs a lab that specializes in rooting out the hidden causes of genetic diseases. In January 2017, his wife showed him a Facebook post about a family in Colorado whose 6-year-old daughter, Mila, had recently been diagnosed with a fatal neurodegenerative condition called Batten disease. Her doctors had identified a single mutation in a gene called CLN7, but the disease should only arise when mutations are present in both copies of the gene—but they couldn’t find the second mutation.
Mila’s mom, Julia Vitarello, had started a group called Mila’s Miracle Foundation to raise money to develop a gene therapy for her daughter. The idea was to deliver a new copy of the CLN7 gene into Mila’s cells. But for that plan to make sense, she needed to be sure that Mila’s second mutation was also on the CLN7 gene.
Yu was intrigued. He reached out and offered to do whole-genome sequencing on Mila, her parents, and her younger brother. Yu reasoned that the missing mutation must be in the so-called “dark matter” of the genome—the 99% of our DNA that doesn’t encode protein-making instructions.
In March, Yu’s team found that a piece of DNA called a retrotransposon—the genetic remnants of viruses scattered throughout all of our genomes—had spontaneously inserted itself in the middle of a noncoding region of Mila’s CLN7 gene. That glitch appeared to prematurely halt the process of RNA splicing, where the coding regions of the gene are stitched together into protein-making instructions. In April , Yu called Mila’s family to share the diagnosis.
Under normal circumstances, Yu’s connection to Mila would have ended there.
But a few months earlier, the FDA had approved a drug called Spinraza, which treats another rare neurodegenerative disease called spinal muscular atrophy. Spinraza uses an antisense oligonucleotide to cover up a mutation that disrupts RNA splicing. It occurred to Yu that an oligonucleotide sequence designed to block the problematic retrotransposon in Mila’s CLN7 gene should also restore her RNA splicing. The project could move relatively quickly by using the same chemical backbone and route of administration as Spinraza.
Inside Yu’s lab, the question quickly turned from “what if we could make ‘Spinraza’ for Mila?” to “why wouldn’t we try?” Yu had three researchers in his lab—April Hu, Aubrie Soucy, and Jai Vaze—begin designing oligos and testing them on Mila’s skin cells. Yu, meanwhile, began talking with the FDA to see what the agency would need to greenlight an experimental oligo drug for Mila.
By September, Yu’s team had picked an oligo—which they called “milasen”—as their lead candidate. It partially restored the abnormal RNA splicing in Mila’s cells in the lab. The FDA asked for a 3-month safety study in rats and Yu, already deep in unfamiliar territory, found himself on the phone with Lauren Black, a scientist at the contract-research company Charles River Labs. Black, who is a former FDA reviewer herself, scurried to assemble a “SWAT team” at Charles River for Yu’s rush order.
In October, Mila and her family visited Boston Children’s Hospital. The hospital wanted to assess both Mila’s condition, and Vitarello’s understanding of the experimental and unproven nature of the therapy. It finally dawned on Vitarello that this “long shot idea might become a reality.”
But the next month, Mila’s health took a downwards turn. She could barely walk without assistance and had become reliant on a feeding tube for food and water. Her already limited vocabulary disappeared. Worst of all, she began having seizures that took all of Vitarello’s strength to control. “We felt she still had a great chance, but in a few months’ time, it might be too late,” she says.
Black told Yu to renegotiate with the FDA. The 3-month safety study in rats, followed by another couple months to report the data, would take too long. After a letter from Vitarello outlining Mila’s decline, the FDA made a concession: Mila could get the drug after just 1 month of testing, so long as the rat studies continued to 3 months to understand any long-term toxicity.
By December, TriLink Biotechnologies had manufactured the drug, but Vitarello was worried that Mila might not even get it. “The company that made it was having cold feet at the last minute,” she says. “And I just felt like Mila was being given this amazing chance and it was all about to get flushed down the toilet.”
Executives from TriLink declined requests for interviews, but according to Richard Snyder, who was the chief scientific officer at Brammer Bio at the time, TriLink shipped the drug substance to his company in early January 2018. Brammer Bio—a firm that specializes in gene therapies and has since been acquired by Thermo Fisher—was to formulate, filter, and fill Mila’s drug into vials.
Brammer Bio finished the job on January 11. Yu’s lab submitted the paperwork to begin human studies of the drug the next day, and the FDA gave its approval a week later, on January 19. Mila got her first injection of the drug at the end January—just 1 year after Yu’s wife had shown him the Facebook post about Mila.
Today, Mila continues to get injections of her drug approximately every 2 months. She used to have up to 30 seizures a day, each lasting more than a minute. Now, she only has a few a day, and they don’t last long, Vitarello says. She has also been eating a lot of her meals by mouth again. But Mila is not cured. She has not been as responsive lately, which has been painful for Vitarello to watch.
Mila lost a lot in those 2 months before she got her drug, Vitarello says. “We were working at the speed of light, so I have no regrets or anger,” she adds. “But obviously in my mind, I wonder if we had given that drug to Mila 2 months earlier, where would she be today?”
Vitarello raises the question because she knows speed is critical for future families developing n-of-1 therapies for rare diseases.
Since Yu shared Mila’s story at the American Society of Human Genetics a year ago, hundreds of families have contacted him asking if a personalized antisense oligonucleotide could help treat a loved one’s rare disease. In public lectures, Yu has acknowledged that he can’t help them all. But his lab is already spearheading the development of several more personalized oligos, including ones for a rare form of epilepsy and a neurological disease called ataxia-telangiectasia—both of which might be ready for injection this year.
Beyond capacity, there’s the not insignificant issue of money. Although Vitarello fundraised $3 million, she says a significant portion of that went to the gene therapy project—which she passed on to another family—and basic research on Batten disease. Yu’s lab and Boston Children’s Hospital picked up a lot of the tab, although it’s difficult to account for the unbilled expertise that dozens of doctors, scientists, and regulatory experts lent to the project. Vitarello and Yu won’t disclose how much it cost to develop milasen. “I don’t want to talk about it, because it takes away from the fact that it was done,” Vitarello says. “But over time, this has to be more accessible.”
FDA officials mobilized to allow Mila to receive her specialized treatment, and in an editorial that accompanies Yu’s paper, FDA directors Janet Woodcock and Peter Marks write that personalized drug-development projects like milasen likely represent the absolute bare minimum preclinical evaluation that investigators can get away with. Situations where several people have a disease, or the disease is less severe, will make for tougher decisions . This summer, FDA approved another n-of-1 clinical trial with an antisense oligonucleotide for a woman with a severe form of ALS—a drug that could one day benefit others with similar forms of ALS.
Mila’s story has become a symbol of hope for other families afflicted by rare diseases and who have no therapeutic options. “I was fighting for Mila,” Vitarello says. But because so many people stood up to help her give her daughter this chance, Vitarello feels a responsibility to help open up a similar path for other families. “Questions need to be faced about patient selection, ethics, and funding,” she says. “And it needs to be scaled. But Mila’s treatment showed that this is possible.”