Abstract

Using RNA Signatures For Therapeutic Development in Amyotrophic Lateral Sclerosis (ALS) and Fronto-Temporal Dementia

Clotilde Lagier-Tourenne, Assistant Professor of Neurology, Massachusetts General Hospital and Harvard Medical School

Expanded GGGGCC repeats in a non-coding region of the C9ORF72 gene are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Several pathogenic mechanisms have been proposed including loss of function from reduced expression of C9ORF72 and/or toxicity derived from the expansion-containing RNAs. Accumulation of nuclear RNA foci and cytoplasmic dipeptide repeat proteins (DPRs) translated from the repeat-containing RNAs are pathological hallmarks of disease in patient cells and mice expressing C9ORF72 RNAs with up to 450 repeats. Indeed, hexanucleotide expansions caused age-, repeat length- and expression level-dependent accumulation of RNA foci and DPRs, accompanied by loss of hippocampal neurons, increased anxiety, and impaired cognitive function in transgenic mice. The presence of pathological hallmarks of C9ORF72 disease and behavioral abnormalities establishes this mouse model as an essential tool to develop novel therapeutic approaches, including RNA-targeting antisense oligonucleotides and immunotherapies for patients with ALS/FTD. Antisense oligonucleotides (ASOs) were identified which reduce GGGGCC-containing nuclear foci without altering overall C9ORF72 RNA levels in patient cells. By contrast, siRNAs failed to reduce nuclear RNA foci despite marked reduction in overall C9ORF72 RNAs. In mice, single dose intracerebroventricular injection of ASOs that target repeat-containing RNAs produced sustained reductions in RNA foci and dipeptide-repeat proteins, and ameliorated behavioral deficits. These findings establish ASO-mediated degradation of repeat-containing RNAs as a significant therapeutic approach for ALS/FTD linked to C9ORF72 expansions.