New ALSA Drug Screening Effort to Search for ALS Therapies

8/2/2005

The ALS Association (ALSA) today announced funding for a collaborative project that will screen thousands of existing compounds for possible activity as ALS therapeutics, using tiny worms living in lab dishes that recreate aspects of amyotrophic lateral sclerosis (ALS). The ALSA-initiated grant gives continued support to the efforts of Richard Morimoto, Ph.D., who has created a worm that expresses the mutant gene for copper-zinc superoxide dismutase (SOD1), responsible for some inherited cases of ALS. Researchers suspect that mutant SOD1 is not folded properly and disrupts the ability of motor neurons to function.

Morimoto, who is at Northwestern University in Evanston, Ill., will collaborate with Cambria Biosciences in Woburn, Mass. to carry out high throughput screening of several libraries of compounds. The collaboration will seek compounds that change the ability of a cell to either correct poorly constructed protein or consign it to the cellular trash heap.

“The collaboration with Cambria Biosciences will allow us to more rapidly identify new lead compounds that interfere with the appearance of misfolded proteins and aggregates and the associated cellular toxicity that ultimately paralyzes the animal,” said Morimoto. “We are very excited that this project brings together the technical expertise of Cambria in high throughput screening with our knowledge on the new animal model system that we have established.” 

Leo Liu, M.D., president of Cambria Biosciences, added that “Dr. Morimoto’s work has laid the foundation for a new approach to ALS therapy discovery. We are very pleased to be able to pursue this translational research project together with ALSA and Dr. Morimoto’s laboratory.”

ALSA funds this collaboration through its program to recruit established investigators to join the search for effective ALS treatments. The collaborative screening effort, using the C. elegans worm model of ALS, is expected to find fresh insight into the basic process of the disease, revealing new targets at which to aim drug discovery efforts.

In close conjunction with ALSA’s new initiative,Translational Research Advancing Therapy for ALS (TREAT ALS), the Morimoto and Cambria collaboration will work with the TREAT ALS drug steering committee to review available compound libraries and to strategize on any promising leads.

The millimeter long worm, C. elegans, is commonly used in the lab to manipulate genes and study the result in a living organism. Morimoto, an expert in Huntington’s disease and on the cellular response to damaged proteins, introduced the gene for SOD1 into the worm, and was able to detect both a change in the way the protein looks in the transparent worm under the microscope, and a change in the worm’s ability to move about, once the mutated SOD1 gene is expressed (see for additional details http://www.alsa.org/news/article.cfm?id=681).

With the worm, and Cambria’s expertise in high throughput screening, investigators will pan for compounds in existing collections that might have unrecognized potential as therapeutics for ALS. The search will be based on changing the cell’s ability to handle proteins. This can be brought about either by assisting with proper protein folding, a task carried out by the molecules called chaperones, or by helping to send mistakenly folded proteins to the disposal system inside cells called the proteosome.  The success of any promising compound in the primary and secondary screening process carried out by the collaboration will then lead to further testing in a rodent model of ALS.

“We are extremely pleased to announce this exciting collaboration between academia and biotech and believe this is the way forward to finding new therapies for ALS”, commented Lucie Bruijn, Ph.D. ALSA science director and vice president.