From The ALS Association
January 5, 2004

In a research project initiated and funded by The ALS Association, a
Histone Deacetylase (HDAC) inhibitor, Scriptaid, and a folate analog DPDTB
(small chemical molecules) were found to inhibit protein inclusions in a
cell model of ALS. Investigator Qing Liu, Ph.D., an instructor at
Massachusetts General Hospital and an ALSA visiting fellow at the
Institute of Chemistry and Cell Biology (ICCB), Harvard Medical School,
recently presented an update on her results in San Francisco during the
annual meeting of the American Society for Cell Biology.

Dr. Liu established an assay system in which protein inclusions formed in
cultured cells expressing mutant Cu/Zn Superoxide (SOD1); these mutations
are linked to 20% of familial ALS. The inclusions are likely the result
of the accumulation of misfolded protein and other cellular proteins that
are involved in misfolded protein degradation. Inclusions morphologically
similar to this are found in several neurodegenerative diseases including
Alzheimer’s disease, Parkinson’s disease and ALS. Whether these protein
inclusions are harmful to the cell remains unknown.

To answer this question, Dr. Liu and her group screened 20,000 small
molecules from several commercially available libraries for inhibitors of
protein inclusions induced by mutant SOD1. These libraries contain small
molecules, most of which have not been developed further for medical use
and would require additional toxicity and safety studies to move toward
FDA approval for particular indications. For more information, refer to
http://iccb.med.harvard.edu. In addition, 1040 compounds from the
National Institute of Neurological Disorders and Stroke (NINDS) custom
collection, about 750 of which are FDA approved, were screened in this
assay.

HDAC inhibitors are a class of compounds functioning through a variety of
mechanisms. Exactly how they may modulate protein inclusion formation is
still under investigation. It is interesting that this class of compounds
showed an effect on increasing survival in a fly model of Huntington's
disease and more recently a mouse model of Huntington’s disease. To
determine whether these compounds prolong survival in ALS, Scriptaid and
DPDTB will be tested with the ALS mouse model.

“We are grateful that ALSA funded this high-risk research project,” said
Dr. Liu. “This study is of great interest to us because it not only
provides us with some very useful tools to understand the basic biology of
protein inclusion formation, but also offers leads for potential
therapeutics.”

“This study was initiated to develop relevant assay systems to screen
compounds for ALS," said Dr. Lucie Bruijn, science director and vice
president of The ALS Association. "The results are promising, especially
as HDAC inhibitors have been tested in other neurological disorders. We
look forward to learning whether they increase the survival of ALS mice.”

Questions and Answers:

1. What is the distinction between the two groups of compounds discussed?

As part of an NINDS/ALSA initiative a collection of 1040 compounds were
identified for screening in a variety of assays. About 750 of these
compounds are FDA-approved. The commercially available libraries used in
this study consist of small molecules that have not been approved by the
FDA for other indications and would need to be further studied for
toxicity and bioavailability. For additional information, refer to the
ICCB web site at http://iccb.med.harvard.edu.

2. What are the names of some of the more promising compounds?

Scriptaid and DPDTB were two of the promising compounds identified in the
commercial library that disrupted accumulations. There are several groups
studying the role of HDAC inhibitors including an ALSA-funded investigator
Fernando Dangond, M.D., Bringham and Women’s Hospital, Boston, MA. (see
http://www.alsa.org/research/awardsci_14Aug03.cfm#HDAC).

3. When could the research move into clinical trials?

As the compounds to be tested in the animal models are not FDA approved,
they would need to be further developed for safety and toxicity profiles.