50 Scientific American, March 2020created a custom antisense drug for one little girl with an ultra-
rare disease in less than a year. “People have been talking about
biologic therapies for 30 years, and what’s extraordinary is it’s
starting to happen,” says neurologist Robert Brown of the Uni-
versity of Massachusetts Medical School, who is a leader in ALS
research. (Biologic drugs are those made from living organisms.)
“This is a true game changer.”
SENSE AND ANTISENSE
dna provides the basic bLueprint for life, but it has to be read and
translated into action through the production of proteins, which
carry out most of the work in the body. Because the instructions
encoded in DNA are so critical, the process of translation has
protective mechanisms built into it. There is a lot of repetition,
beginning with the two strands of nucleotides that zip together
to form DNA’s double helix. One serves as a template, laying
down sequences of the four bases that make up DNA molecules:
adenine (A), thymine (T), guanine (G) and cytosine (C). The oth-
er strand reads that template and lays down a complementary
set of bases. Each base on a strand is always positioned opposite
its specific partner: A always pairs with T, and C with G. To
ensure accuracy, the RNA only ever encodes the instructions in
the nontemplate strand for the creation of proteins. Biologists
call the two strands by a variety of names, including sense and
antisense, which gives the ASO technology its name.
Occasionally the end results—the proteins—do not come out
right. They can be overproduced or underproduced, resulting indisease. Small-molecule drugs, which make up the majority of
pharmaceuticals on the market, target the proteins associated
with diseases. Monoclonal antibodies, the other major class of
drugs, generally bind to proteins and stimulate a patient’s
immune system to attack them. In contrast, the aim with anti-
sense drugs is to disrupt the process earlier. They are designed
to replace faulty RNA during the transcription process by snap-
ping into place according to the standard base-pairing rules
and thereby tweaking protein production.
A parallel effort has focused on what is known as RNA inter-
ference, or RNAi. This technology was discovered just when
antisense had been given up for dead, so its proponents avoided
the term, but the drugs derived from the two approaches are
related. “I think of antisense as the genus and RNAi as a species,”
Bennett says. The difference is that RNAi drugs have two strands,
whereas ASOs have only one. But any chain that is short—usual-
ly 15 to 20 nucleotides—is considered an oligonucleotide.
The versatility of oligonucleotide drug technology derives
from the way it separates two critical elements: the platform orEMMA PLAYING on a swing set near her home. Thanks to the
success of clinical trials of nusinersen involving her and others,
more than 8,400 SMA patients around the world are now taking
the drug. The breakthrough has spurred the field of antisense
therapy, which seems to be particularly effective for neurological
ailments of genetic origin.© 2020 Scientific American