What are Splice Switching Oligonucleotides (SSOs)?
Splice Switching Oligonucleotides (SSOs) are short, synthetic strands of nucleic acids designed to bind to pre-mRNA transcripts and modulate
alternative splicing. By altering the splicing pattern, SSOs can correct aberrant splicing events, potentially restoring the normal function of genes involved in various diseases, including
cancer.
How Do SSOs Work in Cancer Treatment?
SSOs specifically target the splicing machinery of cells, which is often dysregulated in cancer. They bind to specific sequences in the pre-mRNA, blocking or promoting the use of certain
splice sites. This can lead to the inclusion or exclusion of particular exons, thereby producing a functional or non-functional protein. For instance, SSOs can be used to skip mutated exons in tumor suppressor genes like
TP53, potentially restoring their tumor suppressive functions.
Why is Alternative Splicing Significant in Cancer?
Alternative splicing allows a single gene to produce multiple protein variants, increasing the complexity of the
proteome. In cancer, abnormal splicing can lead to the production of oncogenic protein isoforms or the loss of tumor suppressor functions. By targeting these splicing events, SSOs offer a novel therapeutic approach that differs from traditional small molecule drugs or monoclonal antibodies.
Specificity: SSOs can be designed to target specific splicing events with high precision, minimizing off-target effects.
Customization: The sequence of SSOs can be easily modified to target a wide range of genes and splicing events.
Versatility: SSOs can be used to either promote or inhibit splicing at specific sites, offering a high degree of control over gene expression.
Delivery: Efficient delivery of SSOs to target cells remains a significant hurdle. Various methods, including
nanoparticles and viral vectors, are being explored to enhance delivery efficiency.
Stability: SSOs are susceptible to degradation by nucleases in the bloodstream. Chemical modifications, such as
phosphorothioate bonds, can improve stability but may also affect binding affinity and specificity.
Off-Target Effects: Although SSOs are designed for specificity, there is still a risk of off-target binding, which can lead to unintended splicing changes and side effects.
What Are the Current Applications and Future Directions?
Currently, SSOs are being investigated in several preclinical and clinical studies for various types of cancer. For example, SSOs targeting the oncogenic splicing variant of the
BCL2L1 gene have shown promise in treating
leukemia and
lymphoma. Future research is focused on improving delivery methods, enhancing specificity, and exploring combination therapies with existing cancer treatments.
Conclusion
Splice Switching Oligonucleotides represent a promising frontier in cancer therapy, offering a unique mechanism to correct the aberrant splicing events that contribute to cancer progression. While there are challenges to overcome, ongoing research and technological advancements hold the potential to make SSOs a viable option in the fight against cancer.
