Antisense Oligonucleotide-Mediated Splice Switching: Potential Therapeutic Approach for Cancer Mitigation

Area of Science:

• Molecular Biology
• Genetics
• Biochemistry

Background:

• Alternative splicing generates diverse mRNA variants and protein isoforms.
• Aberrant splicing contributes to cancer development and therapeutic resistance.
• Oncogenic splice variants impact crucial cellular processes like apoptosis and proliferation.

Purpose of the Study:

• To review chemical modifications and delivery strategies for antisense oligonucleotides (AOs).
• To discuss the therapeutic potential of AOs in modulating aberrant splicing.
• To focus on AO-mediated exon skipping as a cancer treatment strategy.

Main Methods:

• Review of chemical modifications to enhance AO stability and binding affinity.
• Exploration of various AO delivery strategies for improved cellular uptake.
• Analysis of clinical trial data for AOs targeting cancer-associated splice variants.

Main Results:

• AOs can inhibit oncogenic splice variants via splice modulation or mRNA degradation.
• AO-mediated splice switching can induce premature stop codons, inhibiting oncogenic proteins.
• Six distinct studies demonstrate AO-mediated exon skipping as a viable cancer therapy.

Conclusions:

• Antisense oligonucleotides represent a promising therapeutic approach for cancers driven by aberrant splicing.
• Optimized AO chemistry and delivery are crucial for effective cancer treatment.
• AO-mediated exon skipping shows significant potential in clinical applications for cancer therapy.