NDLI: Development of Therapeutics for C9ORF72 ALS/FTD-Related Disorders

Content Provider	Springer Nature Link
Author	Mis, Maria Sara Cipolat Brajkovic, Simona Tafuri, Francesco Bresolin, Nereo Comi, Giacomo P. Corti, Stefania
Copyright Year	2016
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.
Starting Page	4466
Ending Page	4476
Page Count	11
File Format	PDF
ISSN	08937648
Journal	Molecular Neurobiology
Volume Number	54
Issue Number	6
e-ISSN	15591182
Language	English
Publisher	Springer US
Publisher Date	2016-06-28
Publisher Place	New York
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	Hexanucleotide repeat expansion Haploinsufficiency Antisense oligonucleotides Neurosciences Neurobiology Cell Biology Neurology
Content Type	Text
Resource Type	Article
Subject	Neurology Cellular and Molecular Neuroscience

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