[QUICK SUMMAR:] A consortium of researchers has found that Ceftriaxone, a drug that alters glutamate, has been found to 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.
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 PsychoGenicshttp://www.alsa.org/research/grant.cfm?id=175). 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/.
Clinical Trial Plans - Questions and Answers
Q: Should I ask my doctor to prescribe Ceftriaxone (Rocephin) or another similar antibiotic for me to take?
A: No, the researchers doing this study and other ALS clinical experts agree that it is premature for patients to take Ceftriaxone for ALS. The clinical trial being planned is designed to answer the question of whether or not ceftriaxone is safe when used for long periods of time and has a positive effect for people with ALS. The information published in the January issue of the journal Nature, and described in the ALSA release above, is experimental.
Q: How can I learn more about the clinical trial and find out about enrolling?
A: Planning has begun for a clinical trial of ceftriaxone. The study will be conducted by the Northeast ALS consortium and several other US and Canadian ALS centers. It will be funded by the National Institutes for Neurological Diseases and Stroke (NINDS). It is anticipated that the clinical trial will include 600 people with ALS at 46 ALS centers throughout the
The investigators are currently seeking regulatory (Food and Drug Administration) approval to conduct this clinical drug study. They are hopeful that patient enrollment will begin in the spring or summer of 2005.
The principal investigator of the clinical trial grant from NINDS is Merit Cudkowicz, MD from
The Project Manager for the study is Amy Swartz (firstname.lastname@example.org) from Massachusetts General Hospital. For more information, she can be reached at (617) 726-9122 or by e-mail.