Unc-13 homolog A (UNC13A) pre-mRNA cryptic exon and flanking splice regulatory regions (UNC13A cryptic exon)

The UNC13A pre-mRNA cryptic exon and its flanking splice regulatory regions represent a critical therapeutic target in neurodegenerative diseases characterized by TDP-43 pathology, such as Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD) (Brown et al., Nature 2022). Under normal physiological conditions, the RNA-binding protein TDP-43 binds to specific motifs within the UNC13A pre-mRNA to suppress the inclusion of a cryptic exon (Ma et al., Nature 2022). However, in disease states, TDP-43 undergoes nuclear depletion and cytoplasmic aggregation, leading to the erroneous inclusion of this cryptic exon into the mature UNC13A mRNA (PubMed, 2022). This inclusion typically introduces a premature stop codon, triggering nonsense-mediated decay and a subsequent loss of UNC13A protein, which is essential for synaptic vesicle priming and neurotransmitter release (UniProt, 2024). Therapeutic strategies, primarily utilizing antisense oligonucleotides (ASOs) like QRL-201, aim to bind these regulatory regions to sterically block the splicing machinery and prevent cryptic exon inclusion (Quince Therapeutics, 2023). Restoring functional UNC13A levels is hypothesized to preserve synaptic integrity and slow disease progression in patients with TDP-43 proteinopathy (Nature Communications, 2023).

Other names

UNC13A CEUNC13A cryptic splice siteUNC13A intron 20 cryptic exonUNC13A-CE

Splice modulation via antisense oligonucleotide-mediated steric hindrance to exclude the cryptic exon and restore functional protein expression.