Testing a Potential Treatment for Amyotrophic Lateral Sclerosis (ALS)

Raymond P. Roos, M.D.

University of Chicago0

Grant Program:

Clinical Neuroscience Research

Funded in:

September 2011, for 2 years

Funding Amount:


Lay Summary

Testing a potential treatment for Amyotrophic Lateral Sclerosis (ALS)

Investigators will determine whether a drug that is approved an on the market to treat another condition holds promise for treating fatal Amyotrophic Lateral Sclerosis (ALS).

ALS is a progressive and ultimately fatal disease resulting from the death of nerve cells in the brain and spinal cord, called “motor neurons,” that control voluntary muscle movements. It is often referred to as Lou Gehrig’s disease after the Yankee’s “Iron Man” first baseman, who played a record-setting 2,130 consecutive games before being diagnosed with the disease. Patients develop progressive muscle weakness, eventually become paralyzed, and die within three to five years. Scientists have found that some patients with a rare form of ALS that occurs in families results from a mutant protein (mtSOD1). Moreover, evidence suggests that patients with the sporadic (non-familial) form also may have this mutation. The protein folds incorrectly. Then the misfolded proteins aggregate in motor neurons and sequester other proteins that are essential for the cells’ functioning. The affected motor neurons, however, activate a protective “unfolded protein response,” which may provide a therapeutic opportunity.

Based on initial evidence in a mouse model of familial ALS, the investigators hypothesize that they can ameliorate the disease by enhancing an enzyme (called “PERK”) that is involved in the cells’ unfolded protein response. They will test this hypothesis using two different types of treatments that enhance the PERK enzyme pathway, each via a different process. One of these treatments is the drug guanabenz, (Wytensin®).  It already has demonstrated safety and efficacy for treating hypertension and is approved by the Food and Drug Administration for this use. A few animal studies suggest that the drug also acts on misfolded proteins. The other treatment involves use of genetic techniques to increase PERK. They will study guanabenz and the genetic technique in the animal model of familial ALS. If guanabenz demonstrates effectiveness in the animal model, the investigators then will initiate a study of this drug in a small number of patients with sporadic ALS. They will first test the relative safety of guanabenz at different dosages, and then obtain initial information on the drug’s potential efficacy.  This first in humans study then may lead to a larger clinical trial of guanabenz. Additionally, since misfolded proteins are involved in the prion disease Creutzfeld-Jacob, and are implicated in other neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease, the study may have implications for identifying experimental treatments for these diseases as well.

Significance: This study may lead to the first effective therapy for ALS, and ultimately to a better understanding of how to intervene effectively to prevent or cure this fatal disease.

Investigator Biographies

Raymond P. Roos, M.D.

1976-1982: Asst Prof of Neurology, Univ Chicago, Chicago, IL;

1977-present: Member, Comm of Virology (now called Comm of Microbiology), Univ Chicago; 1980-1981: Res Assoc, Visiting Prof, Dept Cellular, Viral and Molec Biol, Univ Utah, Salt Lake City, Utah;

1982-1986: Assoc Prof, Dept Neurology, Univ Chicago;

1988-1989: Visiting Scientist, Dept. Microbiol and Molec Genet, UC Irvine, CA;

1986-2001: Prof of Neurology, Univ Chicago; Chairman of Neurology (‘96-‘04), Univ Chicago; 2001-present: Marjorie and Robert E. Straus Professor in Neurological Science, Dept Neurology; Member, Comm of Immunology, Comm of Neurobiol, Univ Chicago

Honors : 1990-1994: NINCDS Program Project Review Comm Study Section
1992-1995: Vaccines and Related Biological Products Advisory Comm, U.S. F.D.A. (Chair–‘95)
1994-2001: Editorial Boards: J Neuroimmunol, J Neurovirol
1996-2000: NIH Virology Study Section
1996-2000: Transmissible Spongiform Encephalopathies U.S. F.D.A. Advisory Comm;
1975-1978: Scientific Review Comm, ALS Assn
1999-2000: The National Academy of Sciences Institute of Medicine Committee to Examine “Multiple Sclerosis; Current Status and Strategies for the Future”
2000-2001: Chairman, Scientific Review Comm, ALS Assn
2001-present: Senior Assoc Ed, MedLink
2002-2003: The National Academy of Sciences Institute of Medicine Comm to Examine Prion Research and Policy
2002-2009: National Multiple Sclerosis Society Research Programs Advisory Comm (2007-2009 – Chair); Amer Acad of Neurol Science Comm; Editorial Board: Ann Neurol
2004-2007: Scientific Review Comm, ALS Assn
2004: AAAS Fellow in Medical Science (For studies on the mechanisms of degenerative diseases in viral and non-viral diseases, particularly for studies of picornavirus central nervous system infections); Donald W. Mulder award (given by the ALS Association)
2005: Fellow in Medical Sciences, AAAS
2005-present: Editorial Board, J Virol
2006:Member, Johns Hopkins Society of Scholars