Boston Children's Hospital
A girl with a deadly brain disease received a unique drug that was invented from scratch just for her and in a fraction of the normal time.
Mila Makovec, now eight, was diagnosed with fatal and intractable Batten disease.
In less than a year, doctors at Boston Children's Hospital created the drug tailored to correct specific errors in Mila's DNA.
She is now having much less seizures, although she is not healed.
Batten disease is incredibly rare, progressively worsening and is always fatal.
Mila was three years old when her right foot began to turn inward. A year later, she needed to hold the books close to her face while her vision was fading and at age five she occasionally fell and her walk became unusual.
At six, Mila was blind, could barely speak, and was having convulsions.
The disease can be caused by a series of genetic mutations that prevent cells from breaking down and recycling waste.
Instead, the garbage accumulates and can lead to brain cell death.
The path to therapy
Mila's family received a diagnosis of Batten's disease and they knew it was genetic.
They started a campaign – Mila Miracle Foundation – hoping to cure the incurable.
"I was sitting down to dinner one night and my wife told me that a friend of hers had shared a Facebook post from a family in Colorado seeking help," Timothy Yu told the BBC.
He met Mila in January 2017 and what followed was incredibly fast and unprecedented.
The Boston team sequenced the entire genome – a detailed interrogation – on Mila's DNA, her genetic code, and discovered a unique mutation that was causing her disease.
Having seen the flaw, the researchers thought it would be possible to treat it.
They designed a drug, tested it on Mila cells and laboratory animals, and got approval to use it from the US Food and Drug Administration.
Mila was treated with the drug – called Milasen – on January 31, 2018.
Normal drugs take about a decade and a half to get out of the lab, go through clinical trials, and reach patients.
The US team arrived there in a year.
"When we stop and look back, we are really proud and surprised. Sometimes it is helpful to be naive, and knowing that we had a declining child while we were doing work motivated everyone to move incredibly fast," Yu said.
He added: "We are not aware of another case where another drug has been adapted in this way."
Boston Children's Hospital
What does this mean for Mila?
The drug cannot undo all the damage that was caused.
"I would say that in the first year we were really thrilled. There seemed to be very little progression of the disease," Yu told the BBC.
This is a disease in which the decline is usually inexorable.
The frequency of Mila seizures has plummeted from 15 to 30 a day (usually lasting about two minutes) to zero to 20 a day, usually lasting only a few seconds.
Her family reported that she was erect and swallowing better.
There are signs in the second year of treatment that the disease is advancing again and Mila continues to be closely monitored.
"We believe it is progressing slower than normal and expect it to stabilize further," said Yu.
He believes that if in future cases it is possible to intervene even earlier – when a child is three or four years old – it "could really make a big difference."
How does the medicine work?
The approach used is incredibly intelligent and required a precise understanding of what was going wrong.
A genetic instruction for building a protein was defective in Mila's DNA and the resulting ineffective protein was causing his Batten disease.
To move from DNA to a protein, there is a stage in the middle – a messenger (mRNA) is created that takes DNA instructions in the cell nucleus to where proteins are produced.
But there was a problem with the construction of the messenger.
Not all genetic code in a section of DNA is copied to mRNA – the parts are cut in a process known as splicing.
But in Mila's case, the amendment was going wrong, so the wrong messenger was being made and a defective protein was the result.
The team has developed a drug that adheres to the forming mRNA and prevents it from being cut in the wrong place.
It is the same technology – antisense oligonucleotide therapy – that offers the first hope of treating devastating Hungtinton's disease.
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Details have been published in New England Journal of Medicine.
Boston Children's Hospital
Mila injected the drug into the spinal fluid
How much did all this cost?
How much this highly personalized treatment costs will be one of the main barriers for more people to benefit.
The research team does not say how much it spent on developing the drug.
But Dr. Yu said, "We wouldn't move forward if we didn't find a way to make it accessible.
"The idea of millions of dollars in millionaire drugs doesn't fit well with what we're doing."
Could this be a new approach to medicine?
There are over 7,000 rare diseases caused by genetic abnormalities, which often lack any form of treatment.
Not all rare diseases – or even all patients with Batten disease – could be treated in the same way as Mila.
But the hope is that truly personalized medicine, based on a detailed genetic understanding of what is causing a disease, can lead to this kind of precision treatment.
Janet Woodcock of the US Food and Drug Administration's drug regulator said individualized drugs, known as N-one because they are used by only one person, raise new problems.
She said, "In these 'N-of-one' situations, what kind of evidence is needed before exposing a human to a new drug?
"Even in rapidly progressing fatal diseases, precipitating serious complications or death is not acceptable, so what is the minimum guarantee of safety required?"
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