Antisense oligonucleotide

Antisense oligonucleotides (ASOs) are short, synthetic strands of nucleic acids designed to bind to RNA sequences by following the rules of base pairing. By binding to their target RNA, ASOs can modify the expression of genes at the RNA level, leading to a decrease in the production of specific proteins. This technology is used in research and medicine to study gene function and to treat a variety of diseases.

Mechanism of Action

Antisense oligonucleotides work by binding to the complementary mRNA sequences of a target gene. Once bound, they can recruit RNase H, an enzyme that degrades the RNA strand of the RNA-DNA duplex, effectively reducing mRNA levels and thus decreasing protein synthesis. Alternatively, ASOs can be designed to alter splicing patterns or inhibit protein translation without inducing mRNA degradation.

Design and Synthesis

The design of effective ASOs involves selecting a target sequence that is unique to the mRNA of interest and accessible for binding. The chemical properties of ASOs are often modified to improve their stability, binding affinity, and specificity. Common modifications include the use of phosphorothioate backbones and locked nucleic acids (LNAs).

Applications

Antisense oligonucleotides have been explored for the treatment of various genetic disorders, cancers, and viral infections. For example, they are used in the treatment of spinal muscular atrophy (SMA) with the drug nusinersen, which modifies the splicing of the SMN2 gene to produce more functional SMN protein. Other applications include targeting genes involved in lipid metabolism to treat conditions like familial hypercholesterolemia.

Challenges and Future Directions

Despite their potential, the use of ASOs is limited by challenges related to delivery to target tissues, off-target effects, and immune responses. Ongoing research aims to develop more efficient delivery systems and to enhance the specificity and stability of ASOs.

See Also

• Gene therapy
• RNA interference
• Nucleic acid analogues