June 2012 - The ALS Association Greater Sacramento

Research Update
Page 6
Drug Company Working Group Meeting Attracts Professionals from Academia and Industry to Discuss Therapeutic Opportunities
for ALS
In April, at The American Academy of Neurology Annual Meeting in New Orleans, The ALS Association brought together an overflow
crowd of researchers, industry executives, and many others, all with the common purpose of finding new treatments for ALS. The meeting
of the ALS Drug Company Working Group organized by the Research and Public Policy Departments of The ALS Association was
standing room only, an indication of the broad interest in the research and drug development world in developing treatments for the
disease.
“Our purpose for the meeting was to encourage those in the field and those thinking of getting into it, to talk with each other, and to
share ideas and strategies for fighting ALS. That's what will help us move ahead,” said ALS Association Chief Scientist Lucie Bruijn, Ph.D.
The latest news on the trial of antisense therapy against SOD1 was discussed by Frank Bennett, Ph.D., of Isis Pharmaceuticals, which is
developing the drug for treatment of familial ALS due to SOD1 mutations. Final results of the trial were then presented the following
day by Timothy Miller, M.D., Ph.D., of Washington University in Saint Louis. In this double-blind trial, antisense molecules that bind to
SOD1 messenger RNA were injected into the spinal cord in 21 patients.
The intent of the treatment is to shut down production of SOD1 and alter the progression of the disease in familial ALS. However, Dr.
Bennett said that the trial was meant to establish safety, not test efficacy, and the drug was given only once, rather than multiple times
over a prolonged period, as would likely be needed to have an effect on disease progression. Additional studies would be needed to
determine the efficacy of this treatment.
Drs. Bennett and Miller reported that the trial showed that single doses appeared to be safe with the most important side effects related
to the delivery of the drug, not the activity of the drug once inside the spinal cord. Because it is delivered by lumbar puncture
(injection into the intrathecal space surrounding the spinal cord), treatment is associated with an increased risk of headaches, nausea,
and vomiting.
Tests performed on patients showed that the drug achieved the predicted levels in the cerebrospinal cord and in the blood. “This was
an important trial for studying the intrathecal delivery of antisense oligonucleotides,” Dr. Bennett said, as it was the first time that the
procedure had been performed.
Dr. Miller noted that the antisense molecule targets all types of mutations of SOD1, rather than being mutation-specific, which would
increase its potential utility if it turns out to be effective. Some evidence suggests that normal SOD1 may be involved in sporadic ALS,
and that lowering it may be therapeutic. If so, Dr. Bennett said, antisense therapy may be helpful. He also noted that antisense directed
against the C9ORF72 gene may be therapeutic if it is shown that the disease it causes is due to a new toxic substance, rather than the
absence of normal protein from the gene.
Steve Han, M.D., Ph.D., of Massachusetts General Hospital in Boston, and the Department of Stem Cell and Regenerative Biology at
Harvard University, discussed progress toward the development of ALS models using induced pluripotent stem cells (iPS cells) from patients
with ALS.
In this system, cells are taken from the skin of a patient, grown in a lab dish, and then, by application of a cocktail of growth factors,
transformed into iPS cells, which multiply to make many millions of cells. These cells can then be transformed into motor neurons. The
value of this system is to rapidly create many identical cells for study in the lab, all of which contain the same genetic mutation that
caused the patient's ALS. These cells can be used to learn more about what causes disease and to screen drugs as potential therapies.
The lab has developed iPS cell lines with mutations in SOD1, TDP-43and FUS and has begun development of lines with C9ORF72 and the
ALS risk factor ataxin-2.
FUS (Fused in Sarcoma) is currently a major target of research in the lab. The FUS protein binds RNA, the messenger cells used to translate
genes into proteins. It is normally found in the cell's nucleus, but the mutations that cause ALS relocate it to the cytoplasm in the
cell's periphery. The more FUS is mislocalized, the earlier the disease begins and the more severe it is, Dr. Han said.
Dr. Han is currently comparing cell lines from two different sources with different FUS mutations to understand more about how specific
mutations affect neurons. One notable feature in FUS mutants is their effect on so-called stress granules. These structures appear
in cells in response to stress and are thought to be part of a protective response. In some FUS mutants, though, these granules, which
are in the cytoplasm, appear to be adversely affected by the presence of FUS. Dr. Han is investigating the details of that effect, which
may lead to better understanding of how the mutant causes disease in motor neurons. Continued on page 8.