Current and prospective disease-modifying therapies for amyotrophic lateral sclerosis.
BACKGROUND
Amyotrophic lateral sclerosis (ALS) is a devastating illness of unclear etiology affecting motor neurons. It causes unremitting muscle paralysis, atrophy and death usually within 3 - 5 years from diagnosis. The human and economic costs for those affected are sobering. To date, tremendous efforts have failed to find a cure.


METHODS
An extensive literature search was undertaken using Medline and the Cochrane Systematic Review and Clinical Trial databases. Riluzole and investigational ALS drugs are discussed. Riluzole is the only approved disease-modifying therapy despite its modest effect on survival. Recent research has produced promising agents aimed at better disease control if not a cure. This review discusses agents targeting neuronal glutamate excitotoxicity, protein misfolding and accumulation, autophagy, apoptosis, mitochondrial dysfunction, free radical oxidative injury, immunomodulation, mutant mRNA counteraction, muscle physiology, neurotrophic factors and stem cell applications. The challenges in ALS drug development are highlighted.


CONCLUSIONS
Riluzole should be used for patients with definite, probable, suspected or possible ALS by World Federation of Neurology diagnostic criteria. Systematic monitoring for hepatic dysfunction, neutropenia and other serious adverse effects should be done routinely as outlined. All ALS patients should consider genetic screening and enrollment in ALS trials guided by the data reviewed.
Department of Neurology, Cleveland Clinic Florida, 2950 Cleveland Clinic Blvd., Weston, FL 33331, USA.
John A
JA
Morren
Nestor
N
Galvez-Jimenez
D000690:Amyotrophic Lateral Sclerosis / Q000175:diagnosis / Q000188:drug therapy* / Q000503:physiopathology; D000818:Animals; D002986:Clinical Trials as Topic; D016503:Drug Delivery Systems; D015195:Drug Design; D015507:Drugs, Investigational / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D005820:Genetic Testing / Q000379:methods; D006801:Humans; D018696:Neuroprotective Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D019782:Riluzole / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use
D015507:Drugs, Investigational; D018696:Neuroprotective Agents; D019782:Riluzole