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Gain of Toxicity from ALS/FTD-Linked Repeat Expansions in C9ORF72 Is Alleviated by Antisense Oligonucleotides
Jie Jiang1, Qiang Zhu2, Tania F Gendron3
1Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA 92093, USA; Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA.
Abstract:
Hexanucleotide expansions in C9ORF72 are the most frequent genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. Disease mechanisms were evaluated in mice expressing C9ORF72 RNAs with up to 450 GGGGCC repeats or with one or both C9orf72 alleles inactivated. Chronic 50% reduction of C9ORF72 did not provoke disease, while its absence produced splenomegaly, enlarged lymph nodes, and mild social interaction deficits, but not motor dysfunction. Hexanucleotide expansions caused age-, repeat-length-, and expression-level-dependent accumulation of RNA foci and dipeptide-repeat proteins synthesized by AUG-independent translation, accompanied by loss of hippocampal neurons, increased anxiety, and impaired cognitive function. Single-dose injection of antisense oligonucleotides (ASOs) that target repeat-containing RNAs but preserve levels of mRNAs encoding C9ORF72 produced sustained reductions in RNA foci and dipeptide-repeat proteins, and ameliorated behavioral deficits. These efforts identify gain of toxicity as a central disease mechanism caused by repeat-expanded C9ORF72 and establish the feasibility of ASO-mediated therapy.
Insights
Hexanucleotide repeat expansions in C9ORF72 cause neurodegenerative diseases like ALS and FTD. Antisense oligonucleotides (ASOs) targeting these expansions show promise for therapeutic intervention.
Area of Science:
- Neurogenetics
- Molecular Neurology
- Translational Medicine
Background:
- C9ORF72 hexanucleotide repeat expansions are the primary genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).
- Understanding the precise disease mechanisms driven by these expansions is crucial for developing effective therapies.
Purpose of the Study:
- To investigate the pathogenic mechanisms underlying C9ORF72-associated neurodegenerative diseases.
- To evaluate the therapeutic potential of antisense oligonucleotides (ASOs) in preclinical models.
Main Methods:
- Generation of mouse models with varying C9ORF72 repeat lengths and allele inactivation.
- Assessment of molecular changes, including RNA foci and dipeptide-repeat proteins.
- Behavioral testing to evaluate cognitive and social deficits.
- Administration of ASOs targeting repeat-containing RNAs.
Main Results:
- Absence of C9orf72 caused organomegaly and mild social deficits, but not motor dysfunction.
- Hexanucleotide expansions led to age- and repeat-length-dependent accumulation of toxic species, neuronal loss, and cognitive impairment.
- ASO treatment effectively reduced toxic RNA and protein aggregates and ameliorated behavioral deficits.
Conclusions:
- Gain of toxicity, driven by repeat expansions, is a central mechanism in C9ORF72-related disorders.
- ASO-mediated therapy targeting toxic repeat RNAs is a feasible and promising therapeutic strategy.
