New Study Shows Agent Can Improve Muscle Strength, Size, in Mouse ALS Model
http://www.alscenter.org/news/briefs/090722.cfm

Work adds support to the principle in ongoing human trials.

It's not a cure. But a new tactic to improve quality of life for ALS patients -
one that significantly slows muscle wasting and resulting loss of strength - has
moved forward in the therapy pipeline, thanks to a ground-laying Packard Center
and pharmaceutical company collaborative study.

The work helps support clinical trials that are underway.

In a new study, a research team led by Packard scientists Brett Morrison and
Kathryn Wagner at Johns Hopkins and including industry researchers from
Acceleron Pharma in Massachusetts, found that injecting ALS mice with an agent
that counters the body's own brakes on muscle growth clearly keeps muscles
larger and stronger, either before or after disease symptoms appear.

"What we're doing doesn't prevent motor neuron loss," says Morrison. "But it
does allow existing mouse neurons to innervate muscles that are larger and
stronger. It's compensating, really. And it seems to hide the animals'
deterioration longer."

The work was reported in a recent issue of Experimental Neurology.

In the study, SOD1 mice that mimic one type of ALS in humans were injected with
a mouse version of a soluble protein called ACE031. The protein is a red herring
of sorts, designed to attract natural molecules like myostatin and keep them
from reaching their normal muscle targets. Myostatin and its relatives are part
of an internal check and balance system. The molecules' role is to rein in
muscle growth.

By keeping myostatin tied up, the body is then free to rebuild muscle tissue.

And even though slowing muscle wasting doesn't prevent death, the value of doing
that looks increasingly important to maintain quality of life in patients.
Muscles are important players in energy metabolism as well as in movement.

In the study's first part, ALS mice received rodent ACE031 some 20 days before
symptoms typically appear. Their body weight increased and stayed at that level
until the animals' death. "Remarkably, the animals actually gained strength for
a time after symptoms appeared," Morrison says. That's a time when strength
begins to decline in their untreated mouse counterparts. Test mice were 35
percent stronger. Toward the end of their lives, however, that strength declined
at a slightly faster rate than in control animals - what you'd expect when the
number of motor neurons contacting a larger muscle drops past a certain point.

As for animals injected just as their symptoms were beginning, the figures at
first look less impressive, says Morrison: Muscle strength is only 7 percent
greater than in untreated mice.

"But this means that ACE031 was able to reverse the initial loss of strength and
still go on to increase it."

The timing of the study is especially good, the researchers say, because it
comes as Acceleron just finished the first of its Phase I trials of human ACE031
in healthy human subjects. Phase I trials are designed to show if a treatment is
safe and that people tolerate the trial dosage. Jas Seehar, CSO of Acceleron
Pharma reported at the Parent Project Muscular Dystrophy meeting this June in
Atlanta that ACE031 wasn't toxic and was tolerated.

"Further," says Wagner, "even though Phase I trials aren't designed to show if
an agent actually works, the company reported a demonstrated increase in muscle
mass from a single ACE031 injection. That looks like the first definitive
demonstration that inhibiting myostatin with a drug can increase muscle mass in
people."

New aspects of Acceleron's Phase I trials begin this year.

ACE031 is a human-built molecule whose "business end" is the protein receptor,
found in muscle, for myostatin and its relatives. It has an added bit, part of a
natural antibody that keeps the molecule soluble and prevents it from quickly
deteriorating.