Antisense

Antisense refers to nucleic acid sequences that are complementary to a given sense sequence. In genetics, antisense often denotes two related concepts: natural antisense transcripts that are transcribed from the opposite DNA strand and engineered antisense molecules used to regulate gene expression.

Natural antisense transcripts (NATs) can interact with their corresponding sense RNAs through base pairing and influence gene expression at multiple levels, including transcription, RNA splicing, RNA stability, and translation. Mechanisms include transcriptional interference, RNA duplex formation that alters splicing patterns, masking regulatory elements, and recruitment of chromatin-modifying enzymes. NATs can act in cis, affecting the neighboring gene, or in trans, affecting other targets. The functional relevance of many NATs is still being studied, and they can have both positive and negative regulatory roles.

Antisense oligonucleotides (ASOs) are short synthetic nucleic acids designed to bind specific RNA targets. Depending on chemistry and design, ASOs can recruit RNase H to induce degradation of the target RNA, or act as steric blockers to modulate splicing or block translation. Common chemical modifications increase stability and affinity and reduce immune activation (for example, phosphorothioate backbones and 2'-modified sugars such as 2'-O-methyl or 2'-MOE; more recently, locked nucleic acids are used). ASOs are typically delivered by injection or local administration, and several therapies have been approved for human diseases, including nusinersen for spinal muscular atrophy, which alters SMN2 splicing, and other antisense drugs addressing familial hypercholesterolemia and other conditions.

Limitations of antisense approaches include delivery challenges, off-target effects, variable tissue distribution, and potential immune responses, requiring careful design and monitoring.