A tailormade drug developed in record time may save girl from fatal brain disease

For years, a Colorado couple searched for an explanation for why their bright, active little girl was having increasing trouble walking, speaking, and seeing. In December 2016, Julia Vitarello and Alek Makovec learned that 6-year-old Mila Makovec almost certainly had Batten disease, an inherited and fatal neurodegenerative disorder. Now, in a stunning illustration of personalized genomic medicine, Mila is receiving a drug tailored to her particular disease-causing DNA mutation—and it appears to have halted the condition’s progression.

Today at the annual meeting of The American Society of Human Genetics in San Diego, California, researchers told the story of how in less than a year, they went from sequencing Mila’s genome to giving her a synthetic RNA molecule that helps her cells ignore her genetic flaw and make a needed protein. The same steps could help some other patients with diseases caused by unique mutations in a single gene, they said.

“It’s very exciting,” says gene therapy researcher Steven Gray of the University of Texas Southwestern Medical Center in Dallas, who wasn’t involved in the research. “There couldn’t be a stronger example of how personalized medicine might work in practice.”

Batten disease afflicts an estimated two to four in 100,000 births in the United States. Patients have problems with lysosomes, enzyme-filled sacs within cells that clear waste molecules. Without properly working lysosomes, waste builds up and kills neural cells, causing brain damage and death by adolescence.

When Mila’s doctors in Colorado sequenced the protein-coding part of her genome, they found an error in one copy of a gene called CLN7, which codes for a protein that likely helps move molecules across the membrane of lysosomes. Both copies—one from mom, one from dad—of CLN7 need to be mutated to cause the disease, yet only the one from Mila’s father appeared defective.

Mila’s physicians wanted to take a closer look at her entire genome to confirm that she had the CLN7 form of Batten. But few clinical labs were offering this more expensive analysis. Plus, the time frame to complete such work was at least 4 months, during which Mila’s condition would continue to decline.

Then, one night in January 2017, Cindy Lien, a physician at Beth Israel Deaconess Medical Center in Boston, was on a Facebook group for physician moms when she saw a note that moved her: A friend of Mila’s family posted that Mila needed whole genome sequencing—fast. Lien told her husband, Timothy Yu, a neurologist and neurogeneticist at the Harvard University–affiliated Boston Children’s Hospital whose work involves sequencing autism patients’ genomes. “Let’s help,” he recalls saying.

A month later, Yu’s lab had generated Mila’s whole genome results. Nothing new popped out from a standard analysis. But looking on a computer screen at Mila’s full genome sequence, Yu’s team noticed that a section within the noncoding portion of her mother’s CLN7 gene didn’t line up properly with the normal sequence for the CLN7 gene. By April, tests showed that a roughly 2000-letter stretch of DNA had landed there—a short sequence of DNA known as a retrotransposon that can jump around genomes. This extra DNA caused an error when the CLN7 gene was transcribed into RNA, the instructions for the cell's proteinmaking machinery. As a result, that copy of Mila’s CLN7 gene was producing a shortened and useless lysosomal protein.

Yu decided to try a new type of drug called an antisense oligonucleotide. It can bind to defective RNA, hiding it and tricking cells into producing a normal protein. He found a company that could quickly manufacture an antisense oligonucleotide his team had designed that matched Mila’s CLN7 mutation and worked in her cells. By December 2017, Yu’s team had the drug in hand—dubbed “milasen” for their young patient.

In January, with the U.S. Food and Drug Administration’s approval for a one-patient trial, “We took a deep breath and started” treatment, Yu recalls. His team infused a low dose of milasen into Mila’s spinal fluid, where it would ideally make its way to her brain and fix her neurons, then raised the dose every 2 weeks.

The drug appears to be safe. And although Yu’s team doesn’t yet have biochemical evidence that Mila’s neural cells are making the CLN7 gene’s protein, some of her Batten symptoms have gradually abated. The clearest change is that she now has fewer and milder seizures, Yu reports. They once came 20 to 30 times a day and lasted up to 2 minutes. Now, that is down to five to 12 daily, lasting just a few seconds, Yu says.

Mila, now back home in Colorado, is still blind, can’t speak, and needs help walking. But, “She looks stable” in clinical tests, Yu says. Her mom has noticed that Mila has gained leg and torso strength, can swallow better, and seems more alert—small changes that “are huge for me,” she says. She calls it “unbelievable” that Mila now “might actually have a second chance at life.”

Yu could not say how much it cost to develop the treatment, which Mila will continue to receive every 3 months. But it was covered with a combination of fundraising through her family’s Mila’s Miracle Foundation, Yu’s research support, and Boston Children's Hospital.

Yu estimates that up to 10% to 15% of patients with Batten and other genetic diseases have similar rare mutations involving a misread gene that, once identified, could be targeted quickly with custommade antisense drugs. His team is now working on using the same strategy to treat certain cases of other inherited neurodegenerative disorders, he says. “I think this really does open up a path that could be applied to other genetic diseases.”

*Update, 21 October, 10:15 a.m.: This story has been updated to explain how DNA and RNA are connected.