C&EN's Year in Pharma 2019 .

Boston Children's Hospital



Credit: Katherine Cohen/Boston Children's Hospital

Timothy Yu, Mila Makovec, and her mother, Julia Vitarello, at Boston Children’s Hospital

Two years ago, Timothy Yu was not a seasoned drug developer. The Boston Children’s Hospital geneticist planned on devoting his career to diagnosing genetic diseases, not treating them.

That all changed with a young girl named Mila Makovec.

Yu’s team pinpointed the root cause of Mila’s neurological condition: a genetic mutation that no one had ever seen before. Yu then realized that an antisense oligonucleotide—a short stretch of synthetic DNA—could potentially cover up the offending mutation and treat her disease.

What followed was an unprecedented sprint to design, test, and manufacture a custom drug that was ultimately approved for injection into Mila—all in the span of 10 months. It’s what the field is calling an N-of-1 therapy, and it shattered records for speed and personalization in drug development.

“Tim Yu showed that someone who has never done an antisense oligonucleotide experiment in their life can rapidly develop a customized drug and treat a patient,” says Arthur Krieg, chief scientific officer of the oligonucleotide company Checkmate Pharmaceuticals. “That’s the huge breakthrough that the field has been waiting for. It’s like the first time someone ran a 4-minute mile,” he adds.

And this breakthrough won’t be the last.

Indeed, Yu is spearheading several more N-of-1 oligonucleotide treatments for rare neurological diseases, including two that may be ready for injection this year or early next. “We’ve been contacted by hundreds of families,” Yu says. He can’t help them all, but his work is invigorating several others to pursue N-of-1 therapies.

For instance, this summer, Columbia University physician Neil Shneider began giving an N-of-1 oligonucleotide to Jaci Hermstad, a woman with a rare form of amyotrophic lateral sclerosis. Although it wasn’t designed just for her—it could help other people with the same mutation—the US Food and Drug Administration approved its use just for Hermstad.

Rohan Seth, an engineer in San Francisco, founded the Lydian Accelerator to develop a custom oligonucleotide for his daughter, Lydia, who was born with a rare genetic form of epilepsy. Seth hopes to create a blueprint based on his experience that other families trying to make N-of-1 therapies can use.

It's like the first time someone ran a 4-minute mile.

Arthur Krieg, chief scientific officer, Checkmate Pharmaceuticals

And Rich Horgan, a recent graduate of Harvard Business School, founded a nonprofit called Cure Rare Disease to develop customized CRISPR gene-editing therapies for his younger brother, Terry, and other people with rare forms of muscular dystrophy that oligonucleotides can’t help.

“That so many parents and families are deciding to go it alone shows that the system isn’t working for everybody,” Yu says. “It clearly speaks to this huge, pent-up, unmet need.”

At its annual meeting in October, the Oligonucleotide Therapeutics Society formed a task force to create guidelines for N-of-1 projects. A small number of universities and medical centers are laying foundations for their own N-of-1 oligonucleotide programs. And at least one biotech start-up is quietly working on a business plan to provide the full gamut of services, from genetic diagnosis to N-of-1 drug design.

Many economic, ethical, and regulatory hurdles remain, but Yu showed that N-of-1 drug development is possible. “It is the start of something that will become much more common,” Krieg says. “And the question in my mind isn’t whether there will be tens or hundreds more, but how long will it take us until there are thousands and tens of thousands of Milas?”.