April 25, 2005

A new approach to a therapy for ALS, also referred to as Lou Gehrig’s
disease, has added muscle strength and life span in animal models of the
disease. The gene silencing approach, called RNA inhibition, prevents a
specific gene from making its protein. The target is the enzyme called
SOD1. This mutation appears in some cases of inherited ALS. The fact that
two separate teams working toward an ALS therapeutic have recently
reported similar hopeful findings with RNA silencing strategies shows that
the approach indeed has promise for rapid progress into clinical
application, said Lucie Bruijn, Ph.D., science director and vice president
of The ALS Association (ALSA).

Scientists have created mice that have the mutant SOD1 and also show
symptoms remarkably similar to all types of ALS. Mice with the SOD1
mutation show better grip strength if treated with the RNA therapeutic,
according to the report online April 25 in the Annals of Neurology, by
ALSA funded investigators Timothy Miller M.D. and Don Cleveland, Ph.D., of
the Ludwig Institute at the University of California, San Diego, and
collaborators. Rapid application of this technique to ALS investigation is
part of ALSA’s program to harness new methods toward changing the
disease.]

IN-DEPTH DISCUSSION

Researchers funded by The ALS Association (ALSA) report the additional
success in animal models with a new technique to silence a specific gene.
Investigators reported in the April 25 online Annals of Neurology that
mutant mice modeling ALS, also referred to as Lou Gehrig’s disease, can be
aided by muscle injection of a therapeutic that produces small molecules
of ribonucleic acid (RNA) as it moves inside the supplying nerves.

The treatment acts to silence the gene which codes for a mutated version
of the protein, copper/zinc superoxide dismutase (SOD1). This gene is
changed in some people who have inherited ALS. Mice are available that
express this mutant SOD1, and they show symptoms remarkably similar to all
cases of ALS, inherited or not.

The RNA therapeutic, injected into muscle, preserved grip strength of that
hind limb when treated, as compared to untreated, SOD1 mutant mice. The
fact that three different teams, using different viral delivery systems,
all achieved therapeutic success in mice sends a strong signal of hope for
rapid progress towards clinical testing of the approach, said Lucie
Bruijn, Ph.D., ALSA’s science director and vice president.

The therapeutic targets the gene for SOD1 by producing RNA molecules that
prevent translation of the gene into protein. An engineered virus, called
a vector, carried the instructions to make the RNA. The virus, although no
longer infectious, still retained its ability to enter cells and produces
the silencing RNA within cells.

These researchers, including Timothy Miller and Don Cleveland of the
Ludwig Institute at the University of California, San Diego, collaborating
with Fred Gage of the Salk Institute in La Jolla, California, Brian Kaspar
of the Columbus Children Research Institute in Ohio, and other colleagues,
used an adeno-associated virus to get the RNA therapeutic into cells.

“While safety will be an important initial concern for applying this
therapy to ALS patients, we are enthusiastic about the previous excellent
safety profile of this virus (AAV-2) in humans,” said Miller. “Since
patients present to clinic after development of symptoms, we are very
encouraged by the positive effects we see in animals treated close to the
first signs of disease.”

Two recent reports obtained success in the same mouse model of ALS using
different, lentiviruses to get the RNA produced inside cells (see
http://www.alsa.org/news/article.cfm?id=613).

The two groups reporting prior success both found that mice with the SOD1
mutation live longer and have slower onset of symptoms when treated with
RNA inhibition. One team, Swiss researchers funded by ALSA and
collaborators, injected the RNA construct into the spinal cord. The other
team, a group at Oxford Biomedica, a biotech company in Britain, obtained
positive results with injection of their construct into muscle, as did the
Miller and Cleveland team.

Transport back to the cell bodies, a normal process in nerve cells, may
allow treatment of ALS by injecting muscles. Direct injection of RNA into
the spinal cord would pose practical difficulties for treating the disease
in people, Miller and Cleveland noted in their report.

The therapeutic contained a marker that allowed the scientists to see that
the construct appeared in the spinal cord after injection into muscle.
This suggests that the virus with its gene cargo is taken up from muscle
by the nerve endings and moved back into the nerve cell bodies in the
cord. The amount of SOD1 protein was reduced in the spinal motor neurons
that contained the marker, the researchers verified.

They noted that they cannot rule out that the RNA silencing therapy is
also working by affecting the injected muscle. The exact role of muscle in
ALS is not yet clear. Studies are beginning to focus on this topic, to
determine if muscle cells are instigating damage, or if they are only
reflecting the damage to their supplying nerve cells.

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