PHOTO: MEHMET KUZU672 5 NOVEMBER 2021 • VOL 374 ISSUE 6568 science.org SCIENCET
hree years ago, neurologist Tim Yu
stunned colleagues at the American
Society of Human Genetics (ASHG)
annual meeting with news that in
just 10 months, his team at Boston
Children’s Hospital had developed,
tested, and administered a drug tailored
to the unique genetic mutation causing a
7-year-old girl’s deadly brain disease. The
story of milasen (named for the girl, Mila)
raised hopes for more such personalized
treatments made from short strands of
RNA, known as antisense oligonucleotides
(ASOs), that can overcome a gene’s flaws.
At this year’s ASHG meeting, held online
last month, Yu shared a sobering update:
Mila died earlier this year—tragic evidence
that for neurodegenerative diseases, “it’s
critical to intervene early,” he told a session.
But Yu’s group and others are now ex-
tending the customized ASO approach,
known as “n of 1” because the drug is de-
signed for just one or a few patients. A
foundation has formed to provide the be-
spoke RNAs for free. The U.S. Food and
Drug Administration (FDA) is developing
guidance for testing, manufacturing, and
monitoring the outcomes of the personal-
ized treatments. And at the ASHG meeting,
Yu balanced Mila’s outcome with a more
hopeful tale of another young girl who was
given a custom ASO and has seen her dis-
ease stabilize for now.
Developing a treatment for a genetic dis-
ease is often a multiyear quest. But after
sequencing Mila’s genome, Yu’s team real-
ized she had an extra stretch of DNA in a
gene called CLN7 that disrupted the mes-
senger RNA (mRNA), or protein-building
instructions, made from the gene. Yu re-
alized this could potentially be overcome
by quickly synthesizing an ASO that would
stick to the RNA during its processing into
a mature mRNA, hiding the error so that
Mila’s cells would make protein correctly.
Yu’s team raced to get milasen through
toxicological testing and FDA approval
under a compassionate use protocol for
life-threatening conditions. Mila was al-
ready blind and could not walk withouthelp when the drug was first injected into
her spinal fluid in early 2018. Although it
helped her—she had fewer seizures and re-
gained some muscle strength—her condi-
tion eventually worsened. But her story led
many more families to seek help from Yu,
who estimates that 10% to 15% of people
with inherited diseases have a genetic er-
ror similar to Mila’s that can be treated
with an ASO customized to match the flaw.
Among them was Ipek Kuzu, born in
March 2017 with ataxia-telangiectasia (A-
T), a neurodegenerative condition caused
by a defect in a DNA repair gene. Ipekbegan to receive spinal infusions of a tai-
lored ASO in January 2020, when she only
had mild symptoms, such as a speech de-
lay. Nearly 2 years later, Ipek has had no
worsening of her problems. However, A-T’s
more severe symptoms don’t appear until
about age 5. “It’s still too early to declare
success,” Yu said at the meeting.
Ipek’s father, Mehmet Kuzu, is realistic:
If Ipek doesn’t need a wheelchair until her
late teens, instead of the usual age of 9 or
10, “it will be a very big difference,” he says.
Other children might also benefit. Yu has
come across four A-T children with the
same mutation as Ipek. “We are a little bit
guilty of a misnomer by calling these drugs
individualized,” he said in his online talk.
Similarly, the biotech company IonisPharmaceuticals in 2019 rushed through
regulatory steps to give 26-year-old Jaci
Hermstad a custom ASO for her rare in-
herited early-onset form of amyotrophic
lateral sclerosis (ALS). Seriously ill when
treatment began, she died in May 2020.
However, 10 other ALS patients with the
same mutation have started on the ASO,
jacifusen, and some have had signs of
clinical improvement, says neurologist
Neil Shneider of Columbia University, who
works with the company.
Ionis launched a 64-patient clinical trial
in April to test jacifusen compared with
a placebo. Extending a custom ASO’s use
to other patients helps defray the stagger-
ing cost of safety testing the molecule in
animals—typically more than $1 million.
Early treatment with a custom ASO may
be less crucial for nonprogressive genetic
disorders. Rush University Medical Center
neurologist Elizabeth Berry-Kravis leads
an ASO trial for Angelman syndrome, in
which children develop intellectual dis-
abilities. The drug binds to the mRNA for
a protein that turns off the paternal copy
of gene called UBE3A so the gene is acti-
vated and makes up for problems with the
mother’s version.
In all five participants, her team saw
striking changes, including acquiring new
words and sleeping better, she said at the
ASHG meeting. Although younger children
improved more, teens made gains, too.
“The neurons are all still there, they’re just
not wired right,” Berry-Kravis said.
The trial was halted 1 year ago because
inflammation around the injection site
caused temporary leg weakness in pa-
tients, but it has restarted outside the
United States with a lower drug dose. Such
side effects are one potential obstacle with
ASOs delivered to the spinal cord, retired
Ionis CEO Stanley Crooke cautioned at the
ASHG meeting.
Still, in January 2020 he created the n-
Lorem Foundation to accelerate tailored
ASOs for “ultrarare” disease mutations—
shared by no more than 30 people, too
few to interest most drug companies. It is
working with more than 35 families and
hopes to treat the first patient, a boy with
a developmental disorder caused by an un-
common mutation, early next year.
Academic groups in several countries
are also working on customized ASOs.
Yu cautions that as researchers move for-
ward with more n-of-1 ASO treatments,
they must “avoid raising expectations too
quickly.” But even if the outcome is un-
certain, the risk is worth taking, Mehmet
Kuzu says. With his daughter Ipek’s dis-
ease, “If nothing is done, we know what
will happen.” jBIOMEDICINERNA drugs custommade for rare
diseases face wider test
With tempered expectations, more scientists try to
accelerate “n-of-1” approach
Ipek Kuzu, age 4, receives a custommade RNA
drug for her ataxia-telangiectasia.NEWS | IN DEPTHBy Jocelyn Kaiser