From cryptic exons to neuronal dysfunction: combinatorial antisense makes sense in TAR DNA-binding protein-43 (TDP-43) pathology

In a recent study published in Science Translational Medicine , Guo et al. 1 shed further light on TDP-43 pathology by demonstrating that several transcripts involved in synaptic function and membrane excitability are aberrantly spliced upon depletion of TDP-43. Simultaneous treatment with antisense oligonucleotides targeting these transcripts corrected the splicing abnormalities and restored neuronal function, suggesting that combination therapy could be a promising approach in TDP-43 proteinopathies. 1