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Amyotrophic lateral sclerosis (ALS) is a progressive uniformly lethal neurodegenerative disorder for which there is no known effective therapy. Risk factors for the development of ALS and determinants of age of onset and disease severity are largely unknown. In addition, there are currently no reliable biological markers of disease progression in ALS. Recent genetic and biochemical studies implicate free radical toxicity as a possible cause of familial ALS and by implication sporadic ALS.

The applicants long term objectives are to gain insights into th underlying disease pathogenesis in ALS and to determine whether free radical-mediated toxicity has a significant role in the pathogenesis in ALS. The proposed study will (1) determine risk factors and potential biological markers for ALS and disease severity and (2) determine whether therapeutic intervention with the anti-oxidant, Procysteine, will slow disease progression in patients with ALS. To achieve these goals the applicant will identify specific clinical features and molecular abnormalities which influence age of onset and disease severity in a retrospective cohort study of patients with familial or sporadic ALS(more than 600 patients). Subsequently, the applicant will follow 75 patients with familial or sporadic ALS in a two year prospective cohort study to quantify the natural rate of disease progression and define clinical characteristics, molecular abnormalities, and laboratory-based biological markers of free radical mediated oxidative damage which influence disease severity. The applicant will also determine the pharmacokinetic and pharmacodynamics properties of the anti-oxidant, Procysteine in a phase 1 study in 20 subjects with ALS. This will be followed by a phase II double-blind efficacy trial of Procysteine compared with the anti-glutamate agent Riluzole in 80 subjects with ALS. The study will be designed to determine whether Procysteine treatment slows the progressive deterioration of motor and pulmonary function in patients with ALS and also to assess the effects of this experimental therapy on endogenous antioxidant levels and free radical stress as measured in the cerebrospinal fluid (CSF), blood and urine.

Funded by the NIH National Center for Advancing Translational Sciences through its Clinical and Translational Science Awards Program, grant number UL1TR002541.