Why are some RNA drugs more efficient than others?

A new frontier in drug development.


Although pre-mRNA splicing medicines have a lot of therapeutic potential, little is known about their quantitative mechanisms of action.

A severe genetic disorder called spinal muscular atrophy (SMA) frequently results in the death of an infant. Professor Adrian Krainer of Cold Spring Harbor Laboratory (CSHL) found that RNA splicing adjustments could be used to cure sickle cell disease almost a decade ago. This discovery created new avenues for drug research and resulted in Spinraza, the first successful treatment for SMA.

Now, researchers at CSHL, including Associate Professor Justin Kinney and Professor Adrian Krainer, along with postdoc Yuma Ishigami, have uncovered why some drugs that target RNA splicing work better than others.

RNA splicing determines which parts of genes are used to create proteins. Spinraza, for example, was designed to precisely target the specific spot where it could modify the protein production needed by SMA patients. However, not all drugs that modify splicing are intentionally designed this way. Some, like risdiplam, have been found to alter RNA splicing without a complete understanding of how they do it.

To comprehend the mechanism of action of these medications, the researchers examined the interactions between RNA risdiplam and branaplam. They assessed how these medications affected various variants of their intended targets and splicing across the entire genome. To comprehend how each medication locates its targets inside a cell, they also developed models.

The protein required to treat SMA is produced by RNA splicing changes made by both branaplam and risdiplam, although risdiplam is more targeted. The researchers discovered that risdiplam only binds to RNA in one way, whereas branaplam binds in two ways. This finding may enable researchers to alter branaplam in order to cure Huntington’s disease, another deadly neurodegenerative condition.

The researchers also found that combining medications that target the same gene region but do so in distinct ways frequently produces a better result than administering either medication alone.

CSHL Associate Professor Justin Kinney said, “You get synergistic interactions. We found synergy is a general property of splice-modifying drugs. This might provide a basis for using drug cocktails instead of individual drugs.”

With the aid of this data, researchers may be able to uncover therapeutic combinations that have the potential to enhance patient outcomes, which might result in fresh approaches to treating SMA and other illnesses. For instance, the Krainer lab recently studied pancreatic cancer RNA splicing.

“Our new study provides insights into the action and specificity of splice-modifying drugs,” Krainer says“This should facilitate the development of more effective drugs and drug combinations for a variety of diseases.”

Journal Reference:

  1. Ishigami, Y., Wong, M.S., Martí-Gómez, C. et al. Specificity, synergy, and mechanisms of splice-modifying drugs. Nat Commun 15, 1880 (2024). DOI: 10.1038/s41467-024-46090-5
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