TAR DNA-binding protein 43 loss-of-function phenotype-related RNA (TDP-43 LOF-related RNA)

TDP-43 loss-of-function phenotype-related RNA refers to a class of messenger RNA transcripts that undergo aberrant splicing—specifically the inclusion of non-coding sequences known as cryptic exons—when the TAR DNA-binding protein 43 (TDP-43) is depleted from the nucleus. In healthy neurons, TDP-43 acts as a splicing repressor that prevents these cryptic exons from being incorporated into mature mRNA; however, in neurodegenerative conditions like ALS and FTLD, TDP-43 mislocalizes and aggregates in the cytoplasm, leading to a nuclear loss of function (Ling et al., 2015, Science). This failure to repress cryptic splicing results in the degradation of essential transcripts or the production of truncated, non-functional proteins, most notably Stathmin-2 (STMN2), which is vital for axonal growth and repair, and UNC13A, which is critical for synaptic transmission (Melamed et al., 2019, Nature Neuroscience; Brown et al., 2022, Nature). Therapeutic intervention for this target class primarily involves the use of antisense oligonucleotides (ASOs) designed to block the recognition of cryptic splice sites, thereby restoring the expression of functional proteins. For example, QRL-201 is an investigational ASO designed to rescue STMN2 expression in ALS patients by preventing the inclusion of its TDP-43-dependent cryptic exon (QurAlis, 2023). By addressing the downstream consequences of TDP-43 pathology, these RNA targets offer a precision medicine approach to treating a wide spectrum of TDP-43 proteinopathies where direct targeting of the TDP-43 protein itself has proven difficult.

Other names

Cryptic exon-containing RNATDP-43-regulated cryptic transcriptsSTMN2 cryptic exon mRNAUNC13A cryptic exon mRNAMis-spliced RNA (TDP-43 loss-of-function)

Splice-switching antisense oligonucleotides (ASOs) bind to cryptic splice sites or cryptic exons within the pre-mRNA to prevent their inclusion during processing, thereby restoring the production of full-length, functional protein (e.g., Stathmin-2 or UNC13A).