48 Scientific American, March 2020
A
t her first birthday, emma Larson was not waLking
or standing, but neither are plenty of other kids at
that age. She loved the bouncer her parents set up
in their Long Island, N.Y., home, and she crawled
with gusto. Then, at 13 months, Emma’s legs stopped
working. Her mother, Dianne Larson, snaps her
fingers and says, “It was like that.” Emma stopped
bouncing. Her legs buckled when she pulled herself up to stand. The change in her crawling
was subtler, but when her parents looked at an old video, the difference was obvious—Emma
now covered less ground and struggled to hold her head up.
After a barrage of testing, in July 2014 the Larsons learned
that Emma had spinal muscular atrophy (SMA), a potentially
deadly neurodegenerative disease that strikes mostly children,
robbing them of the ability to walk, talk and, in the worst cases,
breathe. Her motor neurons were dying because of a severe lack
of a protein called SMN (survival motor neuron) in her body.
“You go through the darkest of dark periods,” Dianne says. But
the family was determined to “go down swinging,” says Matt
Larson, Emma’s father. “We were willing to do pretty much any-
thing to combat this terrible disease.”
Not far from the Larsons’ home, at Cold Spring Harbor Labo-
ratory, biochemist and molecular geneticist Adrian Krainer was
engaged in the same fight. He had been investigating the genet-
ic underpinnings of SMA since 2000 and knew the problem was
a missing or mutated essential gene, SMN1. But he also under-
stood that people carry an inactive and potentially salvageable
analogue of that gene, SMN2. By 2004 he had joined forces with
Frank Bennett of Ionis Pharmaceuticals to try to create a drug
capable of altering SMN2 in SMA patients so that it could ulti-
mately generate functional SMN protein, with the aim of amelio-
rating the progression of the disease. To that end, the research-
ers turned to something called antisense oligonucleotides.
First conceptualized more than 40 years ago, antisense oligo-
nucleotides (ASOs) are short strings of chemically modified DNA
or RNA ( oligo in Greek means “few,” and nucleotides are the
structural units that make up DNA and RNA). ASOs are designed
to home in on the RNA strands produced by a problematic gene
and alter the gene’s expression. That is, the ASOs bind to a sec-
tion of the targeted RNA to produce (or, in some cases, stop the
production of ) proteins whose absence (or presence) causes an
ailment. For decades scientists had labored to prove that this
strategy could yield a drug capable of treating or preventing dis-
Lydia Denworth is a Brooklyn, N.Y.–based science writer and
a contributing editor for Scientific American. She is the author
of Friendship: The Evolution, Biology, and Extraordinary Power of
Life’s Fundamental Bond (W. W. Norton, 2020).
IN BRIEF
Antisense oligonucleotides (ASOs) are short strings
of chemically modified DNA or RNA designed to alter
the proteins produced from specific types of RNA.
After decades of struggle, the technology may finally
be achieving its full potential. Antisense drugs seem
to be particularly effective against rare neurological
ailments of genetic origin.
Prion disease, resulting when a protein called
PrP misfolds—creating a template that prompts
more PrPs to deform—kills neurons faster than
any other neurodegenerative illness.
Using ASOs to reduce the density of PrPs in the
brain while it is still healthy could preclude develop
ment of the lethal disease in those with genetic
susceptibility to it.
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