BIO BUSINESSTHE SCIENTISTSTAFFAlthough it’s still not clear what trig-
gers onset of the disease, research over the
past decade—in particular, the cumula-
tive identification of roughly 50 potential
disease-linked genes by multiple research
groups—has unveiled numerous relevant
mechanisms, most of which act in the motor
neurons affected by ALS. These new insights
are allowing drug developers to shift from
downstream pathways, such as inflamma-
tion or muscle weakness, to upstream mech-
anisms more likely to drive the disease.
Many identified mutations occur in
genes coding for RNA-binding proteins,
such as TDP-43 and FUS, involved in
splicing, transcriptional regulation, or
other aspects of RNA metabolism. These
genetic changes can lead to cytoplasmic
aggregation of these proteins and dys-
functional mRNA metabolism. Intrigu-
ingly, most ALS patients, even those with-
out these mutations, have abnormally high
TDP-43 levels, which can lead to RNA
misprocessing, says neuroscientist Clo-
tilde Lagier-Tourenne of Harvard Medical
School. This suggests that targeting these
pathways could one day result in broadly
applicable ALS drugs.
An emerging player in both dysfunc-
tional RNA biology and other mechanisms
of ALS is the gene C9orf72, thought to
encode a protein involved in cell signal-ing. Mutated forms of this gene account
for 25 percent to 30 percent of familial
ALS cases and up to 5 percent of sporadic
cases, making it the largest known genetic
driver of the disease. Its 2011 discovery
was “a key breakthrough in terms of ther-
apeutic development,” says Laura Ferrai-
uolo, a translational neurobiologist at the
University of Sheffield in the UK. Multiple
companies have begun to target the gene
with therapeutics.
Smaller RNAs might also have a role
to play in ALS. The microRNA miR-155 is
upregulated in the spinal cord of ALS patients,
and reducing its levels in SOD1 mutant
mice improved survival and motor func-
tion, says Bill Marshall, CEO of miRagen,
a Colorado-based company developing
the anti-miR-155 compound MRG-107.
He thinks that miR-155 may additionally
be acting in neural support cells, such as
microglia or astrocytes, which also seem to
play a role in the disease.
Proteins misbehave in ALS, too, mis-
folding and aggregating in the cytoplasm
and thereby triggering cellular stress
pathways. The actin regulator profilin 1
clumps in this manner, and the mutated
profilin found in some patients exacer-
bates TDP-43 aggregation, too. That’s
led researchers such as pharmacolo-
gist Mahmoud Kiaei at the Universityof Arkansas for Medical Sciences to
search for compounds to prevent profilin
clumping. Other drug strategies focus on
broader causes of aggregation, such as
nuclear pore defects that result in cyto-
plasmic protein accumulation. Massa-
chusetts-based Karyopharm’s preclinical
compound KPT-350 aims to inhibit the
nuclear pore protein exportin-1 (XPO1)
in the hopes of alleviating this accumu-
lation. “If it works, it will have a huge
impact in showing how basic biology can
be translated to the clinic,” says Chris
Henderson, vice president and head of
neuromuscular and movement disorders
research at pharmaceutical giant Bio-
gen, which has acquired rights to fur-
ther developing the compound.
Such discoveries have aided preclini-
cal research, via the development of new
rodent models such as TDP-43 and pro-
filin-1 mutant mice. And the recent rise
of cellular reprogramming technology
has made it possible to work directly
with patients’ own cells. Researchers can
convert individuals’ skin cells into neu-
rons that recapitulate their specific spi-
nal cord features, such as protein aggre-
gation and RNA metabolism defects,
says Ferraiuolo. The cells have also been
a boon for therapeutic testing, allowing
her and other researchers to screen 300
drugs per patient per d ay.Beyond small molecules
Rather than develop new versions of tra-
ditional compounds, some companies are
exploring entirely novel kinds of drugs.
Antisense oligonucleotides (ASOs), for
example, are designed to bind to the RNA
transcript of a specific gene and trigger its
destruction before translation (see “Wait-
ing for Oligonucleotide Therapeutics,” The
Scientist, December 2016). For years, ASOs
disappointed in clinical trials, often failing
to produce convincing efficacy data. That
changed with Biogen’s recently approved
ASO nusinersen (Sprinraza), which treats
the childhood motor neuron disease spinal
muscular atrophy. Although the disease
and population are different from ALS, that
success has boosted optimism for Biogen’s
continued partnership with Ionis, Spinra-MULTIPLE TARGETS: Companies are trialing a
number of new therapies for ALS, from traditional
small-molecule drugs to oligonucleotide
therapeutics and stem-cell treatments. These
therapies may target one of several processes
linked to ALS, including inflammation of the cell
body 1 , aggregation of proteins in the cell
cytoplasm 2 , defects in nuclear pore complexes
3 , dysregulation of mRNA processing 4 ,
and dysregulation of microRNAs 5. 1
4
2 3 5