Safety and Efficacy of SOD1 Inhibition by Pyrimethamine in Sporadic ALS (SALS)

Synopsis
This study is very similar in design and ideology as the FALS study, but for patients with sporadic ALS (SALS).  Similar confirmations of the SOD1 protein seen in FALS patients has also been identified in SALS patients.  The way the mutant SOD1 molecule becomes toxic to the cell in familial ALS is uncertain.  However, the unfolding of the SOD1 protein is thought to be important. One possibility is that the unfolded protein is thought to interfere with the normal processing system that the cell uses to dispose of large proteins, such as lysosomes and proteasomes, and eventually causes cell death.  In familial disease, both normal type (i.e. wild type) SOD1 proteins and mutant SOD1 proteins co-exist.  However, we now know that wild type SOD1 molecules become unfolded in the presence of mutant SOD1 molecules.  The stimulus for these previously normal molecules to unfold is uncertain but possibilities include an evolving abnormal cellular environment.  In the presence of the mutant SOD1 and its subsequent disruption of the cellular environment, such as impaired control of oxidation, neurofilament function or membrane transport, the normal SOD1 molecules may unfold as a reaction to chemical stress.  Accordingly, lowering of SOD1 levels in sporadic ALS may result in slowing of the disease process.  The basis of this phase I study is to determine if pyrimethamine can lower SOD1 levels in sporadic disease.

Design
Patients will receive up to 75 mg of pyrimethamine for 36 weeks.   Visits to the center are required every 3 weeks. 

Criteria to participate in this study:

• Not taking Riluzole or Coenzyme Q10 or on a stable dose for 30 days
• No evidence of any of the following conditions: malabsorption syndromes, alcoholism, dementia, seizure disorder, folate deficiency, megaloblastic anemia, and impaired kidney function or liver function
• Forced vital capacity of at least 60% predicted
• Presence of tracheostomy or mechanical ventilation is exclusionary
• Not taking any of the following medications: cytosine, arabinoside, methotrexate, daunorubicin, sulfonamides, zidovudine, lorazepam, Coumadin, sulfamethoxazole, trimethoprim or lithium. 

ENROLLMENT TO BEGIN FEBRUARY 2010

This trial is independently funded