Eight-year-old Mila Makovec was diagnosed with a rare,
usually fatal neurological disorder in 2016, but now—thanks to a
"custom" drug that researchers developed specifically for her—many of
Mila's symptoms have been halted or reversed, according to a report published
Wednesday in the New England Journal of Medicine.
Mila's condition
Mila's symptoms began when she was three years old.
Previously a healthy young girl, she began to suffer from frequent seizures—as
many as 30 per day, lasting up to a few minutes each. As the disease
progressed, she lost her eyesight, became unable to stand on her own, and
ultimately needed a feeding tube.
In December 2016, Mila was diagnosed with Batten's disease,
a rapidly progressing neurological disorder. However, Mila's case was unusual,
according to doctors. Batten's disease is recessive, which means it occurs when
a patient inherits two mutated versions of the MFSD8 gene—but Mila has only one
mutated gene. The other was apparently normal, which should have left her
unaffected.
Timothy Yu and colleagues at Boston Children's Hospital
examined Mila's intact MFSD8 gene, and in March 2017, they found it contained a
DNA error that interfered with the production of a key protein.
The good news was that Yu thought he could make a custom
piece of RNA to fix the problem. But such a step would be extraordinarily
expensive. To support the necessary research, Mila's mother established Mila's
Miracle Foundation, and she managed to raise $3 million.
Yu's team was able to develop a new drug, which they called
"milasen," after Mila. They tested it in rodents and consulted FDA,
which in January 2018 permitted doctors to give the drug to Mila.
Doctors administered the drug via spinal tap so it could go
directly into Mila's brain. Within a month, Mila started improving, according
to her mother, Julia Vitarello. Mila started having fewer and shorter seizures
and now rarely needs her feeding tube. Instead, she's able to eat pureed foods.
Mila still can't stand by herself, but when she's held, her neck and back stay
straight.
According to the New York Times, Mila remains very disabled,
and she has lost the last few words of her vocabulary. Vitarello acknowledged
that milasen won't cure Mila, but added that Mila was seven when she received
her fist dose. "What if the next Mila is treated when she is four or
five?" Vitarello asked, adding that milasen's development "is opening
up an entirely new treatment path."
Experts express concern over personalized medicine
Milasen is believed to be the first drug developed for just
one person, but Yu and colleagues acknowledged that they're unsure what may
come next.
According to Rachel Sher, VP of regulatory and government
affairs at the National Organization for Rare Disorders, there are more than
7,000 rare diseases, more than 90% of which have no treatment approved by FDA.
That means there may be thousands of patients in a similar situation as Mila,
and there aren't enough researchers to design customize drugs for all of them,
the Times reports.
And even if there were enough researchers, cost would be a
concern, Steven Joffe, professor of medical ethics and health policy at the
University of Pennsylvania, said. The government wouldn't pay for the drugs,
nor would drug companies or insurers, Joffe said. "Unfortunately, that
leaves it to families. It feels awfully uncomfortable, but that is the
reality."
Janet Woodcock, director of FDA's Center for Drug Evaluation
and Research, expressed concern about how a custom drug's efficacy might be
evaluated. As for cost, Woodcock said, "We have to figure it out,
collectively, because these people are suffering—many of them children. If we
have the scientific ability to develop treatments for these rare diseases, we
should find a way to make the financial side of this work" .
Kim J, Hu C, Moufawad El Achkar C, Black LE, Douville J,
Larson A, Pendergast MK, Goldkind SF, Lee EA, Kuniholm A, Soucy A, Vaze J, Belur
NR, Fredriksen K, Stojkovska I, Tsytsykova A, Armant M, DiDonato RL, Choi J,
Cornelissen L, Pereira LM, Augustine EF, Genetti CA, Dies K, Barton B, Williams L,
Goodlett BD, Riley BL, Pasternak A, Berry ER, Pflock KA, Chu S, Reed C, Tyndall
K, Agrawal PB, Beggs AH, Grant PE, Urion DK, Snyder RO, Waisbren SE, Poduri A,
Park PJ, Patterson A, Biffi A, Mazzulli JR, Bodamer O, Berde CB, Yu TW.
Patient-Customized
Oligonucleotide Therapy for a Rare Genetic Disease. N Engl J
Med. 2019 Oct 9.
doi: 10.1056/NEJMoa1813279. [Epub ahead of print]
Abstract
Genome sequencing is often pivotal in the diagnosis of rare
diseases, but many of these conditions lack specific treatments. We describe
how molecular diagnosis of a rare, fatal neurodegenerative condition led to the
rational design, testing, and manufacture of milasen, a splice-modulating
antisense oligonucleotide drug tailored to a particular patient.
Proof-of-concept experiments in cell lines from the patient served as the basis
for launching an "N-of-1" study of milasen within 1 year after first contact
with the patient. There were no serious adverse events, and treatment was
associated with objective reduction in seizures (determined by
electroencephalography and parental reporting). This study offers a possible
template for the rapid development of patient-customized treatments. (Funded by
Mila's Miracle Foundation and others.).
Courtesy of a colleague
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