March 2020, ScientificAmerican.com 49ease, but they found such serious prob-
lems with toxicity and delivery that many
abandoned it. Yet the few researchers
who pushed on overcame the ob stac les
just in time to benefit from the detailed
information about genetic diseases
revealed by the genomics revolution.
“Antisense is tailor-made for diseases that
have a genetic cause,” says Brett Monia,
who took over as CEO of Ionis in January
from founder Stanley Crooke. “It’s the
epitome of precision medicine.”
Krainer, Bennett and their colleagues
called their SMA drug nusinersen. When
injected into cerebrospinal fluid, it coax-
es the inactive motor neuron gene to
make SMN. With Biogen, they began test-
ing the drug in human clinical trials in
- The Larsons en rolled Emma the day
she was eligible: her second birthday. By
then she could no longer crawl at all. Her
first dose, in March 2015, was followed by
two more doses in quick succession.
In May 2015 Dianne was in her bed-
room while Emma was in the den nearby.
“I hear her calling me, and it’s getting clos-
er and closer,” Dianne remembers. “Next
thing you know she’d crawled from the
den all the way to my bedroom.” Dianne
asked herself, “Did I just see this?” She
picked her daughter up and carried her
back down the hall. Then she re turned to
the bedroom and called, “Emma, come
here.” The little girl crawled into her
mother’s arms. Weeping, Dianne thought,
“We’re on to something here!”
Indeed, they were. The clinical trial
for nusinersen proved so successful that
it ended a year early. The U.S. Food and
Drug Administration approved the drug,
under the brand name Spinraza, in De-
cember 2016. More than 8,400 patients in
40 countries are now taking it. Twenty-
five newborns with the most severe SMA
mutation were given the drug at birth.
They are four years old now—and devel-
oping normally. “If I had done nothing
else but develop Spinraza, it would have
been enough,” Crooke says.
But Spinraza is also exhibit A in support of the argument that
ASOs are finally achieving their full potential. It is the first ASO to
boast such dramatic results and commercial success. The drug
earned Krainer and Bennett the multimillion-dollar 2019 Break-
through Prize. It also put in reach a tantalizing set of neurological
targets such as Huntington’s disease and amyotrophic lateral scle-
rosis (ALS). “We discovered the genetic basis for most of these dis-
eases back in the 1990s,” Bennett says. “It’s taken us 25 years to
translate these really important scientific discoveries into poten-
tial therapeutics. [With Spinraza,] it was breathtaking almost to
realize that we had a technology that could have such a broad im-
pact on patients who have no therapies available to them.”
Like long-distance runners who have been training at altitude,
antisense scientists have put in hard miles to optimize the chem-
istry and delivery of oligonucleotides. Now they are at sea level
and sprinting. More than 100 drugs are in the development pipe-
line for everything from Alzheimer’s disease to hypertension. Not
all will reach the finish line, but, including Spinraza, eight have
been approved so far in the U.S. and Europe, all for rare diseases.
Drugs for Huntington’s and ALS are in the final stages of clinical
trials. In a historic first, a doctor at Boston Children’s HospitalDIANNE AND MATT LARSON with their seven-year-old daughter, Emma. “We’re
on to something here!” wept Dianne in 2015, when Emma, who suffers from spinal
muscular atrophy (SMA), was able to crawl to her within months of receiving the
antisense drug nusinersen (brand name Spinraza).© 2020 Scientific American