[PDF][PDF] RNA toxicity from the ALS/FTD C9ORF72 expansion is mitigated by antisense intervention

CJ Donnelly, PW Zhang, JT Pham, AR Haeusler… - Neuron, 2013 - cell.com
CJ Donnelly, PW Zhang, JT Pham, AR Haeusler, NA Mistry, S Vidensky, EL Daley, EM Poth…
Neuron, 2013cell.com
A hexanucleotide GGGGCC repeat expansion in the noncoding region of the C9ORF72
gene is the most common genetic abnormality in familial and sporadic amyotrophic lateral
sclerosis (ALS) and frontotemporal dementia (FTD). The function of the C9ORF72 protein is
unknown, as is the mechanism by which the repeat expansion could cause disease.
Induced pluripotent stem cell (iPSC)-differentiated neurons from C9ORF72 ALS patients
revealed disease-specific (1) intranuclear GGGGCC exp RNA foci,(2) dysregulated gene …
Summary
A hexanucleotide GGGGCC repeat expansion in the noncoding region of the C9ORF72 gene is the most common genetic abnormality in familial and sporadic amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The function of the C9ORF72 protein is unknown, as is the mechanism by which the repeat expansion could cause disease. Induced pluripotent stem cell (iPSC)-differentiated neurons from C9ORF72 ALS patients revealed disease-specific (1) intranuclear GGGGCCexp RNA foci, (2) dysregulated gene expression, (3) sequestration of GGGGCCexp RNA binding protein ADARB2, and (4) susceptibility to excitotoxicity. These pathological and pathogenic characteristics were confirmed in ALS brain and were mitigated with antisense oligonucleotide (ASO) therapeutics to the C9ORF72 transcript or repeat expansion despite the presence of repeat-associated non-ATG translation (RAN) products. These data indicate a toxic RNA gain-of-function mechanism as a cause of C9ORF72 ALS and provide candidate antisense therapeutics and candidate human pharmacodynamic markers for therapy.
cell.com