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09.2018 | THE SCIENTIST 63

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A New Dawn for ALS Therapies?

After two decades of failure, novel scientific insights and technical

progress are spurring meaningful innovation in the field.

BY JENNY ROOD

I

n 1999, a paper inNature Medicine

reported that mouse models of the

fatal neurodegenerative disorder amyo-

trophic lateral sclerosis fared better with

a simple treatment: a diet supplemented

with creatine, a compound that helps reg-

ulate energy levels in the brain and mus-

cles (5:347–50). That promising, albeit

preliminary, result soon launched not one

but three clinical trials, with a total of 386

patients in the US and Europe. Disappoint-

ingly, the trials revealed that creatine had

no effect in people. It was a familiar out-

come: more than 50 other clinical trials

of potential amyotrophic lateral sclerosis

(ALS) drugs, ranging from lithium to cele-

coxib (Celebrex), have failed.

Also known as Lou Gehrig’s dis-

ease, ALS results from the degeneration

and death of motor neurons, and affects

approximately two to five of every 100,000

people worldwide. ALS’s devastating

symptoms—including progressively wors-

ening muscle weakness and spasming, and

difficulties with speech, swallowing, and

breathing, leading ultimately to paralysis

and death—have led to an intense hunt for

treatments to halt its progression.

Unfortunately, the desire to give

patients hope has often outstripped good

scientific sense. “Many drugs that have

gone into ALS clinical trials shouldn’t have,

because the preclinical data package didn’t

support it,” says Steve Perrin, CEO and CSO

of the nonprofit ALS Therapy Development

Institute (TDI) based in Cambridge, Mas-

sachusetts. Only five of the 420 ALS ther-

apy candidates that his center has retested

in mouse and cellular models have shown

a therapeutic effect.

Progress has been hindered by three

main challenges. First, the disease’s causal

mechanisms are poorly understood. Even

the two ALS treatments currently approved

by the US Food and Drug Administration

(FDA), small-molecule drugs riluzole and

edaravone, have largely mysterious mecha-

nisms of action and targets, and only mod-

estly improve survival and quality of life.

Second, ALS is a highly heterogeneous

disease in terms of origin (90 percent to 95

percent of cases are sporadic rather than

inherited), initial symptoms (patients may

report limb weakness or difficulty in speak-

ing or swallowing), and speed of progres-

sion (some patients live months, others

decades, after diagnosis). This has made it

tricky to model the disease. For many years,

the only available mouse models were those

carrying mutations in SOD1—the first gene

linked to the disorder—which affect only 2

percent of ALS patients.

Finally, there are no quantitative bio-

markers to track disease progression or serve

as clinical endpoints for trials. Currently, phy-

sicians use the subjective ALS Functional

Rating Scale–Revised, which measures 12

motor skills on a five-point scale.

In the past few years, the ALS research

community has gained traction in meet-

ing these challenges. Genetic discoveries

have revealed new pathways involved in

the disease. Enhanced technologies gen-

erate more-realistic models and hypoth-

eses. And new therapeutic approaches,

such as oligonucleotide therapeutics,

have begun to enter the clinic. Together,

these advances have made many research-

ers optimistic that effective treatments are

finally on the w ay.

Shedding light on ALS biology

In addition to riluzole, on the market

since 1995, and edaravone, which the FDA

approved in May 2017, treatment cur-

rently focuses on managing ALS symp-

toms through multidisciplinary care to

increase weight and aid breathing, com-

munication, and mobility, says Merit Cud-

kowicz, director of the ALS Clinic and

chief of neurology at Massachusetts Gen-

eral Hospital (MGH).