title: Development of Therapeutics for C9ORF72 ALS/FTD-Related Disorders.
abstract: The identification of the hexanucleotide repeat expansion (HRE) GGGGCC (G4C2) in the non-coding region of the C9ORF72 gene as the most frequent genetic cause of both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) has opened the path for advances in the knowledge and treatment of these disorders, which remain incurable. Recent evidence suggests that HRE RNA can cause gain-of-function neurotoxicity, but haploinsufficiency has also been hypothesized. In this review, we describe the recent developments in therapeutic targeting of the pathological expansion of C9ORF72 for ALS, FTD, and other neurodegenerative disorders. Three approaches are prominent: (1) an antisense oligonucleotides/RNA interference strategy; (2) using small compounds to counteract the toxic effects directly exerted by RNA derived from the repeat transcription (foci), by the translation of dipeptide repeat proteins (DPRs) from the repeated sequence, or by the sequestration of RNA-binding proteins from the C9ORF72 expansion; and (3) gene therapy, not only for silencing the toxic RNA/protein, but also for rescuing haploinsufficiency caused by the reduced transcription of the C9ORF72 coding sequence or by the diminished availability of RNA-binding proteins that are sequestered by RNA foci. Finally, with the perspective of clinical therapy, we discuss the most promising progress that has been achieved to date in the field.
authors.affiliation: Dino Ferrari Centre, Neuroscience Section, Department of Pathophysiology and Transplantation (DEPT), University of Milan, Neurology Unit, IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Via Francesco Sforza 35, 20122, Milan, Italy.
authors.forename: Maria Sara Cipolat
authors.initials: MSC
authors.lastname: Mis
authors.affiliation: Dino Ferrari Centre, Neuroscience Section, Department of Pathophysiology and Transplantation (DEPT), University of Milan, Neurology Unit, IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Via Francesco Sforza 35, 20122, Milan, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Brajkovic
authors.affiliation: Dino Ferrari Centre, Neuroscience Section, Department of Pathophysiology and Transplantation (DEPT), University of Milan, Neurology Unit, IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Via Francesco Sforza 35, 20122, Milan, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Tafuri
authors.affiliation: Dino Ferrari Centre, Neuroscience Section, Department of Pathophysiology and Transplantation (DEPT), University of Milan, Neurology Unit, IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Via Francesco Sforza 35, 20122, Milan, Italy.
authors.forename: Nereo
authors.initials: N
authors.lastname: Bresolin
authors.affiliation: Dino Ferrari Centre, Neuroscience Section, Department of Pathophysiology and Transplantation (DEPT), University of Milan, Neurology Unit, IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Via Francesco Sforza 35, 20122, Milan, Italy.
authors.forename: Giacomo P
authors.initials: GP
authors.lastname: Comi
authors.affiliation: Dino Ferrari Centre, Neuroscience Section, Department of Pathophysiology and Transplantation (DEPT), University of Milan, Neurology Unit, IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Via Francesco Sforza 35, 20122, Milan, Italy. stefania.corti@unimi.it.
authors.forename: Stefania
authors.identifier: 0000-0001-5425-969X
authors.initials: S
authors.lastname: Corti
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000628:therapy*; D000818:Animals; D000073885:C9orf72 Protein / Q000235:genetics*; D057180:Frontotemporal Dementia / Q000235:genetics / Q000628:therapy*; D015316:Genetic Therapy; D006801:Humans; D016376:Oligonucleotides, Antisense / Q000627:therapeutic use; D034622:RNA Interference
chemical_list: D000073885:C9orf72 Protein; D016376:Oligonucleotides, Antisense
keywords: Antisense oligonucleotides; Haploinsufficiency; Hexanucleotide repeat expansion