Testing a Potential Treatment for Amyotrophic Lateral Sclerosis (ALS)

Raymond P. Roos, M.D.

University of Chicago

Funded in September, 2011: $250000 for 2 years


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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.


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Raymond P. Roos, M.D.


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Raymond P. Roos, MD


Marjorie and Robert E. Straus Professor in Neurological Science


eRA COMMONS USER NAME (credential, e.g., agency login)


EDUCATION/TRAINING  (Begin with baccalaureate or other initial professional education, such as nursing, include postdoctoral training and residency training if applicable.)



(if applicable)



Columbia College, New York, NY




SUNY, Downstate Medical Center, NY

NINDS (Slow Virus Lab), NIH

Johns Hopkins Hospital, MD

Johns Hopkins Hospital, MD











Staff Associate

Neurology residency Neuroimmunology/Neurovirology


A.  Personal Statement: The goal of the present proposal is to clarify the pathogenesis of familial amyotrophic lateral sclerosis (FALS). We will focus on mutant SOD1-induced FALS, and use transgenic mice as models for  this disease.  Our studies will investigate the importance of ER stress, the UPR, and oxidative stress.  Goals of this proposal are to clarify the pathogenesis of ALS and identify new directions for treatment.  I have worked in the field of ALS for over two decades.  It was on my NIH-funded Program Project that the first linkage was made in FALS (which turned out to be linkage to the SOD1 gene).  My lab has extensive experience with both in vitro as well as transgenic mouse studies in FALS.  We were the first investigators to use intramuscular injections of viral vectors in order to deliver genes to motor neurons.  I have served on groups reviewing ALS grants, including chairing an ALS Association Scientific Review Committee.  In 2004, I received the Donald W. Mulder award, which is given by the ALS Association to “ individuals who exemplify the traits of leadership, dedication, and achievement in combating ALS”. I served as Chairman of the Department of Neurology at the University of Chicago for ~8 years.


B. Positions: 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              


C. Selected Peer-reviewed Publications  (from over 140 peer-reviewed publications) most relevant to the current application:

Siddique, T., Figlewicz, D.A., Pericak-Vance, MA., Haines, J.L., Rouleau, G., Jeffers A.J., Sapp, P., Roos, R.P., et al.: Linkage of a gene causing familial amyotrophic lateral sclerosis to chromosome 21 and evidence for genetic locus heterogeneity.  New Engl. J. Med.  324:1381-1384, 1991.

Deng, H.-X., Hentati, A., Tainer, J.A., Cayabyab, A., Hung, W.-Y., Getzoff, E.D., Herzfeldt, B., Roos, R.P., Warner, C., Deng, G., Soriano, E., Smyth, C., Parge, H.E., Ahmed, A., Roses, A.D., Hallewell, R.A., Pericak-Vance, M.A., and Siddique, T. Amyotrophic lateral sclerosis and structural defects in Cu,Zn superoxide dismutase.  Science 261:1047-1057, 1993.

Roos, R.P., Ghadge, G.D., Kang, U.J., Wollman, R., Fishman, P.S., Kalynych, A.M., Barr, E., and Leiden, J.M.  CNS gene delivery by retrograde transport of recombinant replication-defective adenoviruses. Gene Therapy 2: 132-137, 1995.

Roos, R.P., Siddique, T., and Tainer, J.A., Summary of "Superoxide Dismutase (SOD) and Free Radicals in Amyotrophic Lateral Sclerosis and Neurodegeneration" Conference.  Neurology 45:1779-1780, 1995.

Jordan, J., Ghadge, G.D., Prehn, J.H.M., Bindokas, V.P., Toth, P.T., Roos, R.P., and Miller, R.J. Expression of human Cu/Zn superoxide dismutase inhibits the death of rat sympathetic neurons caused by withdrawal of nerve growth factor.  Molec. Pharm.47:1095-1100, 1995.

Ghadge, G.D.*, Lee, J.P.*, Bindokas, B.P., Jordan, J., Ma, L., Miller, R.J., Roos, R.P.  Mutant superoxide dismutase-1-linked FALS: Molecular mechanisms of neuronal death and protection.  J. Neurosci. 17(22):8756-8766, 1997.

Lee, J., Palfrey, C., Bindokas, V.P., Ghadge, G.D., Miller, R.J., and Roos, R.P.  The role of immunophilins in mutant superoxide dismutase-1-linked FALS (familial amyotrophic lateral sclerosis).  Proc. Natl. Acad. Sci. 96:3251-3256, 1999.

Ghadge, G.D., Slusher, B.S., Bodner, A., Dal Canto, M.,Wozniak, K., Thomas, A., Rojas, C., Tsukamoto, T., Majer, P., Miller, R.J., Monti, A.L., and Roos, R.P. Glutamate carboxypeptidase II inhibition protects motor neurons from death in familial ALS (FALS) models. Proc. Natl. Acad. Sci. 100:9554-9559, 2003.

Ghadge, G.D., Wang, L., Sharma, K., Monti, A.L., Bindokas, V., Stevens, F.J., Roos, R.P.  Truncated wild-type SOD1 and FALS-linked mutant SOD1 cause neural cell death in the chick embryo spinal cord. Neurobiol. Dis. 2:194-205, 2006.

Wang, L., Sharma, K., Deng, H.-X., Siddique, T., Grisotti, G., Liu, E., Roos, R.P. Restricted expression of mutant SOD1 in spinal motor neurons and interneurons induces motor neuron pathology. Neurobiol. Dis. 29: 400-408, 2008.

Wang, L., Deng, H.-X., Grisotti, G., Zhai, H., Siddique, T., Roos, R.P.  Wild type SOD1 overexpression accelerates disease onset of a G85R SOD1 mouse.  Hum Mol Genet 18:1642-1651, 2009. PMCID: PMC2667291

Wang, L., Sharma, K., Grisotti, G., Roos, R.P.  The effect of mutant SOD1 dismutase activity on non-cell autonomous degeneration in familial amyotrophic lateral sclerosis.  Neurobiol Dis, 35:234-240, 2009.  PMCID: PMC2706919

Wang, L., Grisotti, G., Roos, R.P.  Mutant SOD1 knockdown in all cell types ameliorates disease in G85R SOD1 mice with a limited additional effect over knockdown restricted to motor neurons. J. Neurochem.  113: 166-174, 2010. 

Wang, L., Gutmann, D.H.., Roos, R.P. Astrocyte loss of mutant SOD1 delays ALS disease onset and progression in G85R transgenic mice.  Hum Mol Genet 20:286-293, 2010.

Wang, L., Popko, B., Roos, R.P. The unfolded response in amyotrophic lateral sclerosis.  Hum Mol Genet 20:1008-1015, 2011.



D. Ongoing Research Support  – No overlap with present proposal


Project Number: 1R21NS067341-01 (co-PIs: Roos and Kay)                                  09/30/2009 – 08/31/2011                   

Agency: NIH/NINDS                                                             

Title:  Phage Display Investigations of TDP-43

Specific Aims: Identify and characterize peptides that bind TDP-43 and predict the cellular interacting proteins.  Identify and characterize single chain fragments of variable region antibodies (scFvs) that can be used to clarify the function of TDP-43 and may have therapeutic potential.


Project Number: 1 R21 NS066175-01A1 (Roos)                                                                               04/01/10 - 03/31/12                

Agency: NIH

Title:  Single chain Fragments of variable regions in the treatment of Familial ALS                                                                        

Goal: Prepare and characterize scFvs directed against wild type and mutant SOD1.


Project Number:  (PI – Soliven, co-I - Roos)                                                                                     05/1/09 - 04/30/11                                   

Agency: NIH/NIAID/Duke University Medical Center                      

Title:  B cell Repertoire in Myasthenia Gravis

Specific Aims: To determine the antigenic target and B cell repertoire in myasthenia gravis.


Project Number: NA (Roos)                                                                                                                                       10/1/10-9/30/11                        .

Title: Non-cell autonomous degeneration in FALS

Agency: ALS Association                                                      

Goal: To characterize non-cell autonomous degeneration in familial ALS


Project Number: 5 R25 NS065744-02 (Roos)                                                                                   03/03/2009 - 02/28/2014

Title: Training grant


Goal: Preparing trainees in Neurology and Neurosurgery for academic research centers


Project Number:  Pilot grant PP1640 (Roos)                                                                                     3/01/2011- 2/29/2012

Title: Saffold virus and demyelination disease

Agency: National Multiple Sclerosis Society 

Goal: Investigate the pathogenesis of SAFV diseases in an experimental mouse model; Develop and evaluate a reliable, highly sensitive RT-PCR assay to detect SAFV genome in CNS tissue from patients with MS

Completed research support over the last 3 years relevant to the present application


Project Number: None (Roos)                                                                                                                                    01/01/2008 - 12/31/2009   

Title: Non-Cell Autonomous Degeneration in Familial ALS

Agency: The Les Turner ALS Foundation                             

Goal: Investigate non-cell autonomous degeneration in familial ALS. 

Specific Aims: To determine whether G85R mutant SOD1 expression in motor neurons, microglia, Schwann cells, and oligodendrocytes contributes to the pathogenesis of MND in mice.


Project Number: 1749 (Roos)                                                                                                                                                08/01/2008 - 07/31/2010                    

Agency: The ALS Association                                               

Title:  Non-autonomous degeneration in FALS                     

Specific Aims: To determine whether G85R mutant SOD1 expression in astrocytes, Schwann cells and endothelial cells contributes to the pathogenesis of MND in mice.


Project Number: MDA4346 (Roos)                                                                                                                07/01/2007 - 06/30/2010

Agency: Muscular Dystrophy Association

Title: Transgenic mouse studies and therapeutic directions in ALS

Specific Aims: To explore the role of the UPR in FALS.