CAG-repeat-containing messenger RNAs (CAG-repeat mRNAs)

CAG-repeat-containing messenger RNAs (mRNAs) are a class of transcripts characterized by sequences of the trinucleotide CAG, which translates into polyglutamine (polyQ) tracts in proteins. While these repeats are present in many normal genes, their pathological expansion is the underlying cause of at least nine neurodegenerative disorders, collectively known as polyglutamine diseases, including Huntington's disease and several spinocerebellar ataxias (Source: NIH, 2023). In these conditions, the expanded CAG repeat leads to the production of toxic proteins and RNA-mediated toxicity (Source: PubMed, PMID: 31064784). Therapeutic interventions, such as antisense oligonucleotides (ASOs) and small molecules, are being developed to selectively target the expanded CAG repeats (Source: Nature Communications, 2023). A major challenge in this field is achieving "repeat-selectivity"—the ability to silence the mutant allele or specific disease-causing transcripts without affecting "other" CAG-repeat-containing mRNAs that are essential for cellular homeostasis, such as the TATA-binding protein (TBP) (Source: Nucleic Acids Research, 2017). Consequently, these "other" mRNAs represent a critical safety boundary and off-target profile for drugs designed to modulate CAG-expansion diseases (Source: Wave Life Sciences, 2022).

Other names

Other CAG-repeat-containing mRNAsPolyglutamine-encoding mRNAsCAG-expansion transcriptsPolyQ mRNAsCAG-repeat transcriptsTrinucleotide repeat mRNAs

Drugs target the expanded CAG repeat sequence within the mRNA to induce RNase H-mediated degradation, inhibit translation through steric hindrance, or modulate splicing, thereby reducing the levels of toxic polyglutamine proteins.