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being to trigger a buildup of tumor suppres-
sor proteins in the nucleus, where they carry
out their anticancer watchdog function. A
decade on, the company’s first clinical candi-
date, a drug for multiple myeloma, is widely
expected to win marketing approval in the
coming months.
Chemists at Karyopharm developed a suite
of XPO 1 inhibitors, including KPT- 276 and a
relative called KPT- 350 , that had an impor-
tant attribute: They crossed the blood-brain
barrier more readily than other candidates.
KPT- 350 proved more potent and less toxic in
preclinical testing, so the firm looked for ways
to use it to treat brain disease and injury.
Lloyd’s and Rothstein’s results piqued the
company’s interest. When Sharon Tamir, its
head of neurodegenerative and infectious
diseases at the time, learned that the Hop-
kins researchers were working with KPT-
276 and not KPT- 350 , she called them up to
propose a collaboration using the “better”
compound. Meanwhile, she began to dis-
tribute KPT- 350 to other groups in Japan,
Belgium, and across the United States. Col-
lectively, those scientists showed the drug’s
neuroprotective effects across a range
of human cell, fly, and rodent models of
ALS, Huntington, and other brain diseases.
For example, treatment with
KPT- 350 preserved the health
of axons, the long, signal-
transmitting extensions of
nerve cells, and improved the
motor functions of mice with
a multiple sclerosis–like con-
dition, a team led by neuroscientist Jeffery
Haines at the Icahn School of Medicine at
Mount Sinai in New York City showed. And
in the Hopkins group’s hands, the drug kept
alive mouse neurons harboring the muta-
tion associated with Huntington.
“There’s still a lot that needs to be explored
about why the nuclear pore complex is so
susceptible to problems in different types
of neurons in different brain regions caus-
ing multiple different diseases,” says Gavin
Daigle, a former postdoc in Rothstein’s lab
who worked on the Huntington project
and helped link disrupted pore function to
Alzheimer’s disease before joining AbbVie
in Cambridge. But he stresses that all the
research is showing one thing: “This is a
pathway that can be targeted.”
The results proved enough to convince Bio-
gen, which bought the rights to test the drug
in humans. “The package of preclinical data
that Karyopharm was able to amass really
justifies the excitement,” says Laura Fanning,
R&D project leader for KPT- 350 at Biogen
(which has renamed the molecule BIIB10 0 ).
“It’s not just a blip of efficacy in one strain
of mice. It’s a broad base of evidence,” she
says. A first-in-human dose-escalation study
of KPT- 350 could begin in ALS patients later
this year. If the drug shows promise against
that disease, Biogen may expand its clinical
testing to other conditions, Henderson says.ALTHOUGH THE DRUG seems to work in the
laboratory, why or how is not at all clear.
“The story started to get murkier as more
data has come in,” notes Haines, now at
Regeneron Pharmaceuticals in Tarrytown,
New York. Initially, most scientists assumed
that because it blocks XPO 1 , the drug pre-
vents proteins such as TDP- 43 from piling
up in the cytoplasm by trapping them in
the nucleus. But last year, Dormann’s team
and another led by Philip Thomas, a bio-
chemist at the University of Texas South-
western Medical Center in Dallas, indepen-
dently reported that TDP- 43 and another
protein called FUS seem to exit the nucleus
by passive diffusion, not through XPO1-
mediated transport. (FUS also clumps in
the cytoplasm of motor neurons in some
patients with ALS or FTD.)
So if KPT- 350 is not acting directly on the
transport system, what is it doing? “It looks
like the drug is targeting some more general
neurotoxic pathway,” Dormann says, “but it
remains to be clarified what the mechanismreally is and which nuclear transport de-
fects we’re correcting with this drug.”
One possibility, recent research suggests,
is that the drug actually targets tiny, dense
packets of protein and RNA that form dur-
ing times of cellular stress. In healthy cells,
those membraneless “stress granules” gener-
ally break down and their components dis-
perse after a viral infection, thermal shock, or
some other environmental insult has passed.
Not so in the diseased neurons of people with
ALS or FTD. In those cells, the stress gran-
ules persist and turn sticky, recruiting pro-
teins such as TDP- 43 and FUS and eventually
transforming into solid, toxic aggregates.
Over the past year, several research teams
have shown that components of the nuclear
transport machinery—including import-
ers, exporters, and parts of the nuclear pore
itself—also can get tangled up in those ag-
gregates. The transportation system falters,
and as more TDP- 43 and other proteins are
added to the stress granules, a feedback loop
takes hold that grinds the molecular traffic to
a halt. “TDP- 43 is not just a victim of nucleo-
cytoplasmic transport defects,” says Wilfried
Rossoll, a neuroscientist at the Mayo Clinic in
Jacksonville, Florida. “It’s also a perpetrator.”In August 2018 , findings from a study led
by neurobiologist Ludo Van Den Bosch of
VIB–Catholic University of Leuven in Bel-
gium suggested that the transport protein
XPO 1 itself may play a role in stress granules.
That means a drug such as KPT- 350 may
serve primarily as a stress granule buster, and
any impact on transport may be secondary.
“Things are more complicated than initially
presented,” says Van Den Bosch, who has col-
laborated with Karyopharm.
The open questions about KPT- 350 have
not discouraged other groups from pursu-
ing additional strategies to sort out nu-
clear traffic problems. In 2017 , for example,
Guillaume Hautbergue and his colleagues
at the University of Sheffield in the United
Kingdom implicated another export fac-
tor in the neuronal loss experienced by
ALS flies with the C 9 orf 72 mutation.
Hautbergue is working on ways to target
that protein to prevent the export of mu-
tant RNAs produced by the gene.
Other researchers are focusing on break-
ing up stress granules. That approach should
free up transport factors and pore proteins
held hostage in those granules, allowing
them to return to their usual posts in the
cell, explains James Shorter, a protein bio-
chemist at the University of
Pennsylvania. He is developing
a way to equip cells with a gene
for making a “disaggregase”
protein and has begun to test
the therapeutic strategy in a
mouse model of ALS.
A few drug companies, including De-
nali Therapeutics of South San Francisco,
California, and Aquinnah Pharmaceuticals
of Cambridge, are looking for small mol-
ecules that can do basically the same thing.
Those therapies may not directly target the
nuclear transport pathway, but they would
get the job done, says Aquinnah co-founder
and Chief Scientific Officer Ben Wolozin,
a neuropharmacologist at Boston Univer-
sity’s School of Medicine, because disman-
tling stress granules helps restore healthy
nuclear transport. “This is all part of an in-
tegrated biological response,” Wolozin says.
Aquinnah hopes to begin to evaluate its
lead compound in ALS patients this year,
about the same time that Biogen is aiming to
get KPT- 350 into the clinic. For now, Biogen
scientists are still trying to pin down what the
drug is doing in various genetic models of the
disease, including the flies with marred eyes.
But to some extent, Henderson says, knowing
the exact mechanism of action doesn’t really
matter. “The relevant experiment,” he con-
cludes, “is in the human patient.” jElie Dolgin is a science journalist based in
Somerville, Massachusetts.“Here’s a drug with a body of rationale, and
we’re optimistic about getting this into trials.”
Chris Henderson, Biogen1 8 JANUARY 2 019 • VOL 363 ISSUE 6424 223
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