Record Drug Development May Save Girl From Fatal Brain Disease

Growing up in Colorado, 6-year-old Mila Makovec was a bright, active child. However, her parents became concerned as Mila developed increased difficulty walking and speaking, and her vision started to fade. In December of 2016, doctors diagnosed Mila with Batten Disease, an inherited neurodegenerative disorder. The prognosis is fatal.

However, her story appears to have a happy ending. Science reports that yesterday in San Diego, at the annual meeting of The American Society of Human Genetics, researchers recounted how in less than a year, they developed a synthetic RNA molecule that helps her cells ignore her genetic flaw to build a needed protein, and have appeared to halt the condition’s progression.

“It’s very exciting,” said gene therapy researcher Steven Gray of the University of Texas Southwestern Medical Center after seeing the presentation. “There couldn’t be a stronger example of how personalized medicine might work in practice.”

The first step for Mila’s doctors in Colorado was to sequence the protein-coding part of her genome. They found an error in one copy of a single gene that codes for a protein that helps molecules move through the membrane of lysosomes, which are enzyme-filled sacs inside of cells that clear waste molecules. In Batten Disease, the waste that builds up in cells due to this malfunction causes damage to neural cells, leading to damage to the central nervous system and ultimately death.

However, in Batten Disease, both copies of the gene (called CLN7) need to be defective to cause the disease. Mila’s genome analysis showed that only her father’s copy of the gene was defective. They needed to look at her entire genome to confirm their diagnosis. However, such analysis was expensive and would take at least four months to complete. Mila would certainly worsen dramatically while they were waiting.

The doctors received a bit of luck that opened the door for Mila’s cure. Cindy Lein, a doctor at Beth Israel Deaconess Medical Center in Boston, saw a Facebook post about Mila’s situation, and was sufficiently moved to bring it to the attention of her husband, Timothy Yu, a neurologist and neurogeneticist at the Boston Children’s Hospital.

Yu decided to help Mila. His lab generated Mila’s entire genome within a month. Yu got the same results as Mila’s doctors when he did a standard analysis, so he looked through her entire genome sequence on his computer screen. He found a defect in her mother’s copy of CLN7, where a retrotransposon (a small, random slice of DNA) was causing Mila’s CLN7 to produce a shortened, useless lysosomal protein.

Yu developed a drug called an antisense oligonucleotide that binds to defective RNA, hiding it and tricking cells into producing a normal protein. He designed one that would match Mila’s mutation, and found a manufacturer that could produce it. By December, 2017, the drug had been produced, and in January the FDA approved it for a single-patient trial.

Yu began to administer the drug to Mila by infusing a low dose into her spinal fluid, then gradually increased the dose. Since beginning the treatment, Mila has seen a 40-85 percent reduction in the number of seizures per day, with a 98 percent reduction in their longevity. Mila has gained leg and torso strength, can swallow better, and seems more alert. She still has a long way to go in her recovery, but may get a second chance in life.

“I think this really does open up a path that could be applied to other genetic diseases,” Yu said.