Oligonucleotide Therapy

Oligonucleotide Therapy designates therapeutic approaches employing short synthetic DNA or RNA sequences, typically 13-30 nucleotides in length, that bind to specific complementary nucleic acid targets through Watson-Crick base pairing, modulating gene expression or protein production to treat diseases caused by aberrant genetic function. The pharmaceutical industry has developed multiple approved oligonucleotide drugs including nusinersen for spinal muscular atrophy, inotersen for hereditary transthyretin amyloidosis, and eteplirsen for Duchenne muscular dystrophy.

Mechanism categories include antisense oligonucleotides binding messenger RNA to block translation, promote RNA degradation, or modulate splicing, small interfering RNAs triggering RNA interference pathway degrading target mRNA, and aptamers folding into three-dimensional structures binding proteins. Chemical modifications prove essential, with phosphorothioate backbones increasing nuclease resistance, 2' sugar modifications improving stability, and locked nucleic acid modifications enhancing target binding affinity. Delivery represents a critical challenge, with hepatic targeting relatively successful through N-acetylgalactosamine conjugation, while other tissues require lipid nanoparticles or alternative delivery technologies. As chemistry advances and delivery technologies expand tissue accessibility, oligonucleotide therapy continues maturing as a major therapeutic modality.