title: Current developments in gene therapy for amyotrophic lateral sclerosis.
abstract: BACKGROUND
  Amyotrophic lateral sclerosis (ALS) is a devastating adult neurodegenerative disorder characterized by motor neuron degeneration and death around 3 years from onset. So far, riluzole is the only treatment available, although it only offers a slight increase in survival. The complex etiology of ALS, with several genes able to trigger the disease, makes its study difficult.
  
  
  METHODS
  RNA-mediated or protein-mediated toxic gain-of-function leading to motor neuron degeneration appears to be likely common pathogenic mechanisms in ALS. Consequently, gene therapy technologies to reduce toxic RNA and/or proteins and to protect motor neurons by modulating gene expression are at the forefront of the field. Here, we review the most promising scientific advances, paying special attention to the successful treatments tested in animal models as well as analyzing relevant gene therapy clinical trials.
  
  
  CONCLUSIONS
  Despite broad advances in target gene identification in ALS and advances in gene therapy technologies, a successful gene therapy for ALS continues to elude researchers. Multiple hurdles encompassing technical, biological, economical and clinical challenges must be overcome before a therapy for patients becomes available. Optimism remains due to positive results obtained in several in vivo studies demonstrating significant disease amelioration in animal models of ALS.
authors.affiliation: University of Sheffield, Sheffield Institute for Translational Neuroscience (SITraN) , 385 Glossop Road, Sheffield, S10 2HQ , UK.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Scarrott
authors.forename: Saúl
authors.initials: S
authors.lastname: Herranz-Martín
authors.forename: Aziza R
authors.initials: AR
authors.lastname: Alrafiah
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Shaw
authors.forename: Mimoun
authors.initials: M
authors.lastname: Azzouz
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000503:physiopathology / Q000628:therapy*; D000818:Animals; D000073885:C9orf72 Protein; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D015316:Genetic Therapy; D006801:Humans; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology; D009410:Nerve Degeneration; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D000072105:Superoxide Dismutase-1
chemical_list: D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; D009414:Nerve Growth Factors; D011506:Proteins; C000606290:SOD1 protein, human; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1
keywords: adeno-associated virus; amyotrophic lateral sclerosis; gene therapy; self-complementary adeno-associated virus serotype 9