Testing a Potential Treatment for Amyotrophic Lateral Sclerosis (ALS)

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.