Antisense therapy

Antisense therapy is a form of treatment that involves the use of antisense oligonucleotides (ASOs) to interfere with the gene expression process, thereby inhibiting the production of specific proteins that contribute to disease. This therapeutic approach targets the messenger RNA (mRNA) molecules that carry genetic information from DNA to the protein-making machinery of the cell. By binding to these mRNA molecules, antisense oligonucleotides can effectively block their translation into proteins or modify the processing of the mRNA, leading to a decrease in disease-causing proteins.

Mechanism of Action

Antisense therapy utilizes short strands of DNA or RNA that are complementary to specific sequences of mRNA. When these antisense oligonucleotides bind to their target mRNA, they can induce various effects:

• RNase H-mediated degradation: Some ASOs recruit the enzyme RNase H, which recognizes the DNA-RNA hybrid and degrades the RNA strand of the hybrid.
• Steric blocking: ASOs can also block the translation machinery or splicing factors, preventing the synthesis of the protein or altering the splicing of the mRNA.
• Splice switching: By binding to specific sites on the pre-mRNA, ASOs can modulate the splicing process, leading to the production of different protein variants that may be less harmful or more beneficial.

Applications

Antisense therapy has been explored for a variety of diseases, including genetic disorders, cancer, and infectious diseases. Some notable applications include:

• Duchenne Muscular Dystrophy (DMD): ASOs are used to skip specific exons in the dystrophin gene, allowing for the production of a functional albeit shorter dystrophin protein.
• Spinal Muscular Atrophy (SMA): Treatment involves modifying the splicing of the SMN2 gene to increase the production of full-length SMN protein, which is crucial for the survival of motor neurons.
• High cholesterol: ASOs targeting the mRNA of proteins involved in cholesterol regulation, such as PCSK9, have been developed to reduce cholesterol levels.

Challenges and Future Directions

While antisense therapy offers a promising approach to treating a range of diseases, several challenges remain:

• Delivery: Efficiently delivering ASOs to the target cells and tissues without degradation is a major hurdle.
• Off-target effects: Specificity is crucial, as binding to non-target mRNAs can lead to unintended side effects.
• Immune response: The introduction of synthetic oligonucleotides can sometimes trigger immune reactions, which need to be managed.

Researchers continue to explore novel delivery methods, including nanoparticles and viral vectors, to improve the efficacy and safety of antisense therapy. Additionally, ongoing advancements in the design and chemical modification of ASOs aim to enhance their stability and target specificity.

See Also

• Gene therapy
• RNA interference
• Pharmacogenomics