The Scientific Advisory Board of The Robert Packard Center for ALS
Research at Johns Hopkins has awarded new grants to two scientists --
each expert in a new avenue of research the Center will follow in the
coming year.

Here we describe the studies that Zuoshang Xu, M.D., Ph.D., from the
University of Massachusetts Medical School, and Ronald W. Oppenheim,
Ph.D., of the Wake Forest University School of Medicine, will carry out
as the Center's newest scientists.

"DISARMING" AN ALS GENE

Scientists have uncovered more than 90 different types of mutation in
the much-studied gene -- called SOD1-- that goes awry in certain
inherited forms of ALS. And they know, from mouse models that carry the
mutated human gene, that it triggers some as-yet undeciphered chain of
events that destroys motor neurons.

Because people with this inherited form of ALS typically carry normal
SOD1 genes as well as mutant ones, a safe, sure way to shut off the
mutant form -- in theory -- could stop the disease. Blocking the action
of mutant SOD1 would then leave the cells with remaining, normal SOD1,
whose usual role is to help protect them from a variety of assaults due
to buildup of cell toxins.

For the past year, neuroscientist Zuoshang Xu has been refining a hot
new technique in molecular biology with the potential of silencing
mutant SOD1 genes. Using the method called RNA interference (RNAi), he's
"disarmed" trial mutant SOD1 in laboratory test mixtures.

In the approach, he creates small, double-stranded RNA molecules that
can slip through cell membranes and, functionally, act like a
well-targeted monkey wrench to disrupt the specific gene's activity.
These small, interfering RNAs (siRNAs) target molecular intermediates in
the reactions a gene directs and triggers their destruction. The
technique mimics a natural method cells use to quiet genes.

In his Center work, Xu will extend and refine his studies to silence a
larger number of SOD1 mutations. He'll also work on synthesizing the
optimal small RNA molecules. As part of groundwork for possible
therapies, Xu will begin testing the RNAi technique on SOD1 mouse models
of ALS.

BLOCKING DEATH'S PATHWAY

When ALS kills motor nerves, it unleashes a process that ultimately
trips a destructive program hard-wired into motor neuron cells.
Programmed cell death has been eyed as a possible target for therapy for
ALS and other neurodegenerative diseases, and scientists have singled
out certain steps on that downward path as being potentially more useful
than others to disrupt.

One such stage involves the action of a gene called Bax -- one
neuroscientist Ronald W. Oppenheim has recently studied in hopes of
saving nerve cells. His results so far are interesting. When Oppenheim
studied mice lacking the Bax gene, he found they greatly resisted a
natural "sweep" of certain no-longer-necessary neurons that's part of
normal embryo development. To his surprise, however, the rescued nerve
cells failed to connect properly with target muscles after the mice were
born, or to integrate into the spinal cord networks that carry out motor
function.

To increase chances of connection, Oppenheim next injected the mice
with a substance called GDNF (glial derived neurotrophic factor), which,
in nature, encourages the meeting of nerve cells and their muscle
targets. With GDNF, most of the nerve cells appeared normal and the
number of cells with proper muscle connections jumped.

In his Center work, Oppenheim will again study mice without the Bax
gene, only this time in mouse SOD1 models of ALS. He'll monitor
neuromuscular function and motor nerve behavior in the mice to see if
lacking Bax protects the mice, if it's in some way harmful or if
ALS-like changes appear. Should nerve cells be protected from death but
fail to connect with muscle, he'll then test GDNF's ability to correct
that and do follow-up studies to explain precisely what's happening.

THE CENTER FOR ALS RESEARCH
The Center for ALS Research at Johns Hopkins is a collaborative effort
by some of the best ALS and non-ALS scientists to aggressively and
rapidly develop new treatments and find a cure for ALS, also know as Lou
Gehrig's disease. It's the only institution of its kind dedicated
solely to the disease. Research conducted by the Center is meant to
translate from bench to bedside in a expedited time frame. Center
scientists from institutions around the world have made some of the most
important discoveries in ALS, leading to advances in understanding and
treatment of the disease.

The nature of ALS shapes the Center's aggressive, results-oriented
scientific approach. ALS is a divesting, progressive neuromuscular
disease that causes complete paralysis and loss of function -- including
the ability to eat, speak, and breathe -- and eventually, death. ALS
progresses quickly and is not curable. Most patients die within five
years of diagnosis.

To learn more about the Center for ALS Research at Johns Hopkins,
including the latest information on ALS research and treatment, log on
to www.alscenter.org