[Dysphagia] Screening effort of drug and ALS

[bonnieh4455 at sbcglobal.net (Bonnie Heintskill)]

Screening Effort Identifies Ceftriaxone as Potential ALS Therapeutic



[QUICK SUMMARY: A screening consortium has revealed a previously unknown
property of an existing drug, to alter glutamate transporter protein
expression, and prolong survival in animal models of ALS.]



Researchers have published results in the January issue of the journal
Nature, on a potential new treatment route for patients with amyotrophic
lateral sclerosis (ALS), using an already marketed drug. Unexpectedly, the
compound alters the levels of a protein that regulates the nerve cell
messenger, glutamate. Now the drug, called ceftriaxone, is about to enter
clinical testing in ALS.



"We now have a candidate going to clinical trials, due to this unique effort
that brought drug screening into the academic arena," commented ALSA science
director Lucie Bruijn, Ph.D., who is an author on the paper.



Originally designed to target microbial metabolism, many of the beta lactam
class of compounds can also affect glutamate transporter protein expression.
Glutamate is a critical messenger for the central nervous system. It is kept
at proper concentrations by means of a transporter molecule, called EAAT2,
which collects any excess. Scientists funded through a consortium effort
discovered that several beta lactams can affect the readout of the gene
coding for the EAAT2 transporter and thereby influence levels of glutamate.



The revelation about this action of beta lactam drugs came about through a
concerted effort to screen existing compounds for potential in
neurodegenerative diseases. "These studies document a new property of a very
common antibiotic," write the researchers, "and demonstrate that beta
lactams can activate the gene for a neurotransmitter transporter."



The drug screening effort was initiated as a joint project of The ALS
Association (ALSA), the National Institute of Neurological Disorders and
Stroke (NINDS), the Hereditary Disease Foundation (HDF), and the
Huntington's Disease Society of America (HDSA). Investigators from 26
laboratories took part in the initial 6-month, $1.3 million project, which
tested 1,040 compounds using 29 different assays, or tests
http://www.alsa.org/news/article.cfm?id=284.



Drug companies frequently conduct rapid drug-screening programs that examine
many thousands of compounds at a time. The effort that revealed the
glutamate action of beta lactams is noteworthy in that it was publicly
funded, involved primarily academic researchers, and targeted drugs already
approved by the FDA.



Already marketed drugs have significant advantages compared to newly
identified compounds because they have undergone years of use in humans.
This means that they could be immediately available for testing in patients
if the data from the drug screen look promising. A clinical trial in ALS of
ceftriaxone is slated to start in the spring.



Drugs that show statistically significant activity in multiple assays are
especially promising candidates for tests in animal models. Ceftriaxone was
one of these compounds. Led by investigator Jeffrey Rothstein, M.D., Ph.D.,
at Johns Hopkins, the team found that ceftriaxone increased levels of the
glutamate transporter protein, at concentrations known to reach the brain.



Spinal cord tissue taken from nine day old rats, provided the initial
screen. The investigators confirmed the action in living rats and went on to
show that the drugs work to turn on the gene that codes for the transporter
protein. Ceftriaxone was able to raise the amount of transporter protein in
the brains of rats for three months, the maximum duration of administration
tested.



The team then turned to various test tube models of neural injury and found
the drugs effective in preventing cell death.  Finally, they studied the
drugs in the SOD1 mutant mouse model of ALS, in experiments co-funded by
ALSA, NINDS, the Packard center, and Project A.L.S. (The animal testing was
performed at PsychoGenics
http://www.alsa.org/research/grant.cfm?id=175&&CFID=1377719&CFTOKEN=71273851).
Ceftriaxone delayed loss of muscle strength and body weight when treatment
began at disease onset, 12 weeks of age in the mice. Earlier treatment did
not add to the effect. Survival was prolonged similarly, for about ten days,
by treatment that began at either 12 weeks or at six

weeks of age.



Mice who were treated beginning at 70 days showed less glial scarring, and
had more motor neurons surviving, after two weeks of treatment, compared to
untreated mutant SOD1 mice, the researchers also found.



Early treatment would not necessarily produce longer survival, Rothstein and
colleagues wrote, as the loss of transporter is not evident until around 90
days in these animals.

Rothstein and collaborators have organized a trial of ceftriaxone in ALS,
funded by the National Institutes of Health. Details of the trial, including
clinical sites and start dates, will be available by spring 2005.



To read a news release from Johns Hopkins Medicine on this research, visit
http://www.hopkinsmedicine.org/Press_releases/2005/01_05_05.html.



For information from the Robert Packard Center for ALS Research at Johns
Hopkins, visit http://www.hopkinsmedicine.org/alscenter/.





The ALS Association's new, updated website offers patients, their families,
caregivers and healthcare professionals resources to better understand and
work with ALS. Visit www.alsa.org/patient for more information.