CAG-repeat containing genes (CAG genes)

CAG-repeat containing genes are a heterogeneous group of genetic targets characterized by the presence of unstable cytosine-adenine-guanine (CAG) trinucleotide repeats within their coding regions (Fan et al., 2014, PubMed: 24623157). These repeats encode for polyglutamine (polyQ) tracts in the resulting proteins, which, when expanded beyond a pathological threshold, lead to protein misfolding and the formation of toxic intracellular aggregates (Orr & Zoghbi, 2007, PubMed: 17506644). This group includes genes such as Ataxin-1 (ATXN1), Ataxin-2 (ATXN2), Ataxin-3 (ATXN3), Ataxin-7 (ATXN7), the alpha 1A subunit of the voltage-gated calcium channel (CACNA1A), and the TATA-box binding protein (TBP). Mutations in these genes are the primary cause of several neurodegenerative disorders, collectively known as polyglutamine diseases, including various Spinocerebellar Ataxias (SCAs) and Dentatorubral-pallidoluysian atrophy (DRPLA). Therapeutic development for these targets primarily focuses on reducing the levels of the toxic mutant protein using antisense oligonucleotides (ASOs) or RNA interference (RNAi) (Biogen, 2024, Pipeline). For instance, BIIB105 is an investigational ASO designed to reduce Ataxin-2 protein levels for the treatment of Amyotrophic Lateral Sclerosis (ALS) (Ionis Pharmaceuticals, 2024, Pipeline). A significant challenge in targeting these genes is the need for allele-specific silencing to avoid the potential toxicity associated with the loss of the essential wild-type protein function.

Other names

Polyglutamine disease genesPolyQ genesTrinucleotide repeat expansion genesCAG expansion genes

Antisense oligonucleotide-mediated degradation of target mRNA to reduce the production of toxic polyglutamine-expanded proteins.