Girl facing fatal brain disease gets tailor-made drug

Mila Makovec, pictured at age 2, was diagnosed with Batten disease at age 6. (Photo by Cliff Grassmick/Digital First Media/Boulder Daily Camera via Getty Images))

When Mila Makovec was diagnosed with a rare neurological condition at age 6, her prognosis was grim. The condition, known as Batten disease, is fatal, with death usually occurring in late childhood or the early teen years. There is no cure, and at the time of Mila's diagnosis, in 2016, there was no specific treatment for her condition.

But that soon changed. In a striking example of personalized medicine, doctors were able to develop a tailor-made genetic treatment for Mila and to initiate the therapy, all within a year of first seeing the patient, according to a new report of her case, published today (Oct. 9) in The New England Journal of Medicine. That's much shorter than the years or even decades it typically takes to develop new drugs.

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What's more, the therapy appears safe, and Mila is showing signs of improvement; in particular, she is having shorter and fewer seizures than before, the report said. However, it's unclear exactly how much the treatment will help Mila in the long run or whether it will prolong her life.

Still, the report's authors, from Boston Children's Hospital, said that her case can serve as a "template" for the rapid development of tailored genetic treatments. "This report shows a path to personalized treatments for patients with orphan diseases," the authors said, using a term for diseases that affect fewer than 200,000 people in the nation.

The study was funded in part by Mila's Miracle Foundation, a charity started by Mila's family to find a cure for Batten disease and other devastating neurological diseases.

Devastating diagnosis 

As an infant and young toddler, Mila appeared healthy, learning to walk at age 1 and "talking up a storm" by 18 months, her mother, Julia Vitarello, wrote on the Mila's Miracle Foundation website. But as she grew older, her parents noticed some concerning signs. At age 3, her right foot started to turn inward and she would get stuck on words when talking. At age 4, she started pulling books closer to her face when looking at them, and at age 5, she began stumbling and falling backward.

Shortly before she turned 6, she was hospitalized for a rapid progression of symptoms, including vision loss, frequent falls, slurred speech and difficulting swallowing. Tests showed that her brain volume was shrinking, and she was having seizures, the report said.

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Further lab and genetic testing finally led to her diagnosis: She had Batten disease, a rare and fatal genetic disorder of the nervous system that can take several forms depending on the specific genetic mutation involved. But all forms of the disease appear to affect structures inside cells known as lysosomes, which function as the cell's "trash can" or "recycle bin," breaking down waste products to be discarded or recycled, according to the National Institutes of Health. Without  properly working lysosomes, junk material builds up, leading to cell death, including the death of brain and eye cells.

A detailed analysis of Mila's genome revealed that she had a unique mutation in a gene called CLN7, which is known to be associated with Batten disease. The authors found that a chunk of extra DNA had inserted itself into the CLN7 gene. This meant that when the cell tried to read the gene's instructions to make a protein for the lysosome, the instructions were getting prematurely cut off, preventing the cell from making the full protein.

Doctors realized that a type of genetic treatment that uses molecules called antisense oligonucleotides might work for Mila's case. These are short, synthetic molecules of genetic material (known as nucleic acids) that bind to the patient's faulty genetic instructions, essentially masking the error so the full protein can be produced, according to Boston Children's Hospital.

Doctors named the drug they created "milasen" after Mila. It resembles a recently approved drug for spinal muscular atrophy called nusinersen (brand name Spinraza).

Studies of samples of Mila's cells suggested that milasen could help rescue the lysosome function, and studies in animals suggested there would be no harmful side effects, the report said.

After the doctors received approval from the Food and Drug Administration for a one-person trial of milasen, Mila started treatment in January 2017. The drug was given as an injection into her spinal cord.

Results from the first year of her treatment suggested an improvement in seizures. Before the study, Mila experienced about 15 to 30 seizures per day, each lasting up to 2 minutes, as measured by reports from her parents. But over the course of her treatment, that frequency dropped to between zero and 20 seizures per day, and the duration decreased to less than 1 minute, the authors said.

Measures of Mila's brain waves also showed a decline of greater than 50 percent in the frequency and duration of the seizures. The treatment didn't cause any harmful side effects.

Personalized medicine

Mila's treatment "offers great hope," Vitarello wrote on the foundation website. "While we remain cautiously optimistic, we feel so fortunate that Mila was given a second chance."

Still, before Mila began the therapy, she lost the ability to see, speak and walk without assistance, and the treatment has not reversed these effects, Science Magazine reported.

Although friends have asked if Mila is now cured and will be able to have a normal life, "it's not that simple," Vitarello said. "Batten disease affects every part of the brain and body. It's unbelievably complicated and still very un-understood."

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The authors noted that milasen is still an experimental drug, adding that it is not suited to treat other people with Batten disease, because it is specifically tailored to Mila's unique mutation.

Still, Mila's case suggests that antisense oligonucleotides "may deserve consideration as a platform for the rapid delivery of individualized treatments," the authors said. They noted that antisense oligonucleotides are customizable and have a relatively simple manufacturing process. However, the rapid approach used in Mila's case should be considered only in the context of very serious or life-threatening circumstances, the authors said.

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Originally published on Live Science.