TAR DNA-binding protein 43-regulated RNA transcripts (TDP-43-regulated RNA transcripts)

TAR DNA-binding protein 43 (TDP-43)-regulated RNA transcripts, most notably Stathmin-2 (STMN2) and UNC13A, are critical downstream targets in the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). In approximately 97% of ALS cases, the RNA-binding protein TDP-43 is depleted from the nucleus and aggregates in the cytoplasm, which disrupts its essential role in suppressing the inclusion of non-functional "cryptic exons" during pre-mRNA splicing. This failure leads to the production of truncated, non-functional mRNA transcripts and a subsequent loss of proteins vital for axonal repair and synaptic integrity. Therapeutic interventions, particularly splice-switching antisense oligonucleotides (ASOs), are designed to bind these specific pre-mRNA sequences and prevent the inclusion of cryptic exons, thereby restoring the expression of full-length, functional proteins. This approach, exemplified by clinical candidates like QRL-201, aims to provide a disease-modifying benefit to the broad population of ALS patients who exhibit TDP-43 pathology, regardless of their genetic background.

Other names

TDP-43-regulated RNA transcriptsCryptic exon-containing transcriptsTDP-43-dependent splicing targetsStathmin-2 (STMN2) pre-mRNAUNC13A pre-mRNA

Splice-switching antisense oligonucleotides (ASOs) that bind to pre-mRNA to exclude cryptic exons and restore functional mRNA and protein expression.