C9orf72 Repeat Expansion

Category: biomarker

The most common genetic cause of ALS and frontotemporal dementia. A GGGGCC hexanucleotide repeat expansion in the C9orf72 gene causes ~40% of familial ALS.

Mechanism Detail

The repeat expansion causes disease through three mechanisms: (1) loss of C9orf72 protein function (autophagy regulation), (2) toxic RNA foci that sequester RNA-binding proteins, and (3) repeat-associated non-ATG (RAN) translation producing toxic dipeptide repeat (DPR) proteins (poly-GA, poly-GP, poly-GR) that impair nucleocytoplasmic transport.

Clinical Status

ASO therapies targeting the repeat RNA (WVE-004, BIIB078) in Phase I/II trials with mixed results. AAV-based gene therapies in development. Poly-GP in CSF serves as a pharmacodynamic biomarker.

Relevant Diseases

• ALS

Relevant Therapies

• Gene Therapy

Related Terms

• TDP-43
• SOD1
• Antisense oligonucleotide
• Dipeptide repeats