2002 Sheila Essey Award for ALS Research

Sheila Essey Award Winner Serge Przedborski
Examining the role of apoptosis and inflammation in ALS and the potential for therapies

April 17, 2002

Serge Przedborski, MD, Ph.D., Columbia University, New York, New York is the 2002 winner of The Sheila Essey Award for ALS Research. He received the award on April 16 during the American Academy of Neurology Annual Meeting in Denver, Colorado.

Dr. Przedborski has for some time used the transgenic SOD1 mouse model to determine the events that occur at the onset of ALS and during disease progression. Results from these studies have provided the rationale to test therapeutic compounds in the SOD1 mouse model.

Introduction: Apoptosis is a term given to describe a mechanism of programmed (controlled) cell death involving a large number of recently identified molecules present in cells and activated in a cascade during the cell death process. (A cascade is a series of steps or stages that once initiated continues to the final step by virtue of each step being triggered by the preceding one, sometimes with cumulative effect.) Identifying these molecules and determining the time points when they are expressed or triggered, enables investigators to find targets to prevent or slow disease progression. Caspases are group of closely related molecules involved in apoptosis and play a key role in central nervous system disorders featuring cell death.

Dr. Przedborski has demonstrated in his studies that the molecules involved in apoptosis are present early in the disease process, prior to cell death, making them promising targets to prevent motor neuron death. Recent reports provide evidence for elevated levels of caspase-3 in human ALS. In addition, levels of caspase 1 are elevated in SOD1 mice and human ALS spinal cord.

Inhibitors of these molecules have been identified and used to determine whether suppression of or interference with components of the cell death pathway will slow disease progression in a model of ALS. These published results show that an inhibitor of caspases, zVAD-fmk does indeed increase survival of SOD1 transgenic mice. Unfortunately these compounds are toxic at higher doses required for human studies. Efforts to find safer and effective forms of these compounds are ongoing.

More recent studies have shown that molecules involved in apoptosis may also be involved in inflammation. [Caspase-1 is believed to be involved in inflammation as well as the cell death process.] There is an increase in the number of studies linking the role of inflammatory molecules to neurodegeneration. One key enzyme involved in inflammation is known as Cox-2 (cyclooxygenase type 2). Dr. Przedborski's studies of the SOD1 transgenic mice show that markers for inflammation are increased as compared with normal mice and that these increases coincide with cell loss. Cox-2 activity is significantly increased in postmortem spinal cord from sporadic ALS patients and in the SOD1 mouse model.

Preliminary results to test inhibitors of this inflammatory pathway indicate that a compound blocking Cox 2 shows an increase in survival of SOD1-mutant mice. This compound, Celebrex, is now being used in clinical trials for ALS.

Current Project: In a current ALSA-funded investigator initiated project entitled Experimental Therapies in SOD1-Linked ALS, Dr. Przedborski has used transgenic mouse models to determine the role of apoptosis in ALS. Elevating levels of a protein Bcl-2, which is known to protect against programmed cell death, significantly delays onset and increases the life span of SOD1 transgenic mice. In a similar effort, Friedlander showed that blocking a protein (interleukin-1? converting enzyme- ICE) that is known to promote cell death also increases the lifespan of mutant SOD1 transgenic mice.

To better design experimental therapies, this project will (1) explore the basis of the protective effect of Bcl-2 and ICE inhibition and (2) assess whether the Bcl-2 beneficial action can be enhanced by combining it with other effective therapies. Expression levels of Bcl-2 will be determined in the spinal cord of transgenic G93A mice at different disease stages and compared with normal age-matched littermate controls. This work provides a comprehensive set of experiments that should shed light on the importance of modulating cell death pathways in an effort to develop new avenues of treatments for ALS.

Dr. Przedborski has published extensively in 2000-2001 and has acknowledged ALSA's support in 18 publications.

Because there is still so much to learn about the connection between apoptosis, inflammation and neurodegenerative diseases, ALSA will be holding a workshop on this topic as a satellite meeting at the 2002 Society for Neuroscience Annual Meeting in Orlando this November. Dr. Przedborski will be chairing the meeting. Meanwhile, efforts to fund the most promising projects focusing on inflammation are ongoing as part of ALSA's Lou Gehrig Challenge Initiative.

The Sheila Essey Award for ALS Research

In 1996 The ALS Association in partnership with the American Academy of Neurology inaugurated the Sheila Essey Award for ALS Research to acknowledge and honor an individual actively engaged in ALS research who has made (is making) significant contributions in research in the search for the cause, treatment, prevention or cure for amyotrophic lateral sclerosis (ALS). The recipient receives a $25,000 prize to be used specifically for continuing his/her ALS research. Funding of the award is made possible through The Essey Family Fund and The ALS Association.

The award was conceived by Richard Essey, an ALSA Trustee, whose wife Sheila was diagnosed with ALS in 1994. Richard Essey saw the award as a means to increase the scientific level of interest in ALS.

Through this award The ALS Association, The Essey Family Fund and the American Academy of Neurology wish to focus scientific and public attention on the challenges faced in ALS research and how vital such research is in understanding and arresting this devastating disease. It should be noted that the date (April 16) of this year's presentation of The Sheila Essey Award occurs on Sheila Essey's birthday.

The nominating process and selection of the winner is under the direction of the American Academy of Neurology as part of its annual Scientific Awards Program.