title: Antisense oligonucleotide therapy for the treatment of C9ORF72 ALS/FTD diseases.
abstract: Motor neuron disorders, and particularly amyotrophic lateral sclerosis (ALS), are fatal diseases that are due to the loss of motor neurons in the brain and spinal cord, with progressive paralysis and premature death. It has been recently shown that the most frequent genetic cause of ALS, frontotemporal dementia (FTD), and other neurological diseases is the expansion of a hexanucleotide repeat (GGGGCC) in the non-coding region of the C9ORF72 gene. The pathogenic mechanisms that produce cell death in the presence of this expansion are still unclear. One of the most likely hypotheses seems to be the gain-of-function that is achieved through the production of toxic RNA (able to sequester RNA-binding protein) and/or toxic proteins. In recent works, different authors have reported that antisense oligonucleotides complementary to the C9ORF72 RNA transcript sequence were able to significantly reduce RNA foci generated by the expanded RNA, in affected cells. Here, we summarize the recent findings that support the idea that the buildup of "toxic" RNA containing the GGGGCC repeat contributes to the death of motor neurons in ALS and also suggest that the use of antisense oligonucleotides targeting this transcript is a promising strategy for treating ALS/frontotemporal lobe dementia (FTLD) patients with the C9ORF72 repeat expansion. These data are particularly important, given the state of the art antisense technology, and they allow researchers to believe that a clinical application of these discoveries will be possible soon.
authors.affiliation: Dino Ferrari Centre, Neuroscience Section, Department of Pathophysiology and Transplantation (DEPT), Neurology Unit, University of Milan, IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Policlinico, via Francesco Sforza 35, 20122, Milan, Italy.
authors.forename: Giulietta
authors.initials: G
authors.lastname: Riboldi
authors.forename: Chiara
authors.initials: C
authors.lastname: Zanetta
authors.forename: Michela
authors.initials: M
authors.lastname: Ranieri
authors.forename: Monica
authors.initials: M
authors.lastname: Nizzardo
authors.forename: Chiara
authors.initials: C
authors.lastname: Simone
authors.forename: Francesca
authors.initials: F
authors.lastname: Magri
authors.forename: Nereo
authors.initials: N
authors.lastname: Bresolin
authors.forename: Giacomo P
authors.initials: GP
authors.lastname: Comi
authors.forename: Stefania
authors.initials: S
authors.lastname: Corti
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy* / Q000235:genetics; D000073885:C9orf72 Protein; D042622:DNA Repeat Expansion; D057180:Frontotemporal Dementia / Q000188:drug therapy* / Q000235:genetics; D006801:Humans; D009046:Motor Neurons; D016376:Oligonucleotides, Antisense / Q000627:therapeutic use*; D011506:Proteins / Q000235:genetics*
chemical_list: D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; D016376:Oligonucleotides, Antisense; D011506:Proteins