Spliceswitching

Spliceswitching is the regulation or manipulation of pre-mRNA splicing to alter the pattern of exon inclusion or exclusion, producing different mature mRNA isoforms and, consequently, different protein products. The term covers both natural regulatory processes that switch splice site choice and experimental or therapeutic methods designed to induce such switches.

Mechanisms governing spliceswitching include splice-switching antisense oligonucleotides (ASOs), which bind target RNA to block or enhance recognition of splice sites, exons, or regulatory elements such as exonic or intronic splicing enhancers and silencers. Depending on the target, ASOs can promote exon inclusion or skipping. Other strategies involve small molecules that modulate spliceosome components or splicing regulatory proteins, and emerging technologies such as RNA-targeting CRISPR systems or ribozymes in research settings. Delivery, tissue distribution, and off-target effects remain important challenges in practical applications.

Applications and examples of spliceswitching span basic research and medicine. In research, it is used to study gene function by altering isoform expression. In therapeutics, it enables treatments for diseases caused by aberrant splicing. The most prominent example is nusinersen (Spinraza), an ASO that increases SMN2 exon 7 inclusion to compensate for SMN1 loss in spinal muscular atrophy. Exon-skipping therapies targeting dystrophin exons (for Duchenne muscular dystrophy) and other targets are in clinical use or development. The field continues to pursue new targets, optimized chemistries, and improved delivery methods.

See also: Alternative splicing; Spliceosome; Antisense oligonucleotide therapy.