Cracking the Code: New Insights into RNA Splicing Drugs

Researchers at Cold Spring Harbor Laboratory (CSHL) have uncovered the reasons why some RNA splicing-modifying drugs tend to work better than others, potentially paving the way for more effective treatments for a wide range of diseases.

Spinal muscular atrophy (SMA), the leading genetic cause of infant death, was once considered an incurable condition until CSHL Professor Adrian Krainer’s pioneering work led to the development of Spinraza, the first effective treatment for the disease. This breakthrough opened up a new frontier in drug development by targeting RNA splicing, a process that determines which gene segments are used to build a protein.

Now, Associate Professor Justin Kinney, Krainer, and postdoc Yuma Ishigami have taken this research a step further by analyzing the interactions between RNA and two recently approved SMA drugs, risdiplam and branaplam.

“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.”

Through their analysis, the researchers found that risdiplam is more specific in its interactions with RNA, while branaplam binds to RNA in two different ways, which could help researchers alter its chemical structure to potentially treat Huntington’s disease, a currently incurable neurodegenerative disorder.

Additionally, the study revealed that combining splice-modifying drugs targeting the same gene segment in different ways often has a greater effect than either drug alone, a finding that could lead to new therapeutic strategies using drug cocktails.

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

As researchers continue to explore the potential of RNA splicing drugs, this CSHL study offers valuable insights that could accelerate the development of more effective treatments for SMA, Huntington’s disease, and other diseases.

#RNASplicing #SpinalMuscularAtrophy #Huntington’sDisease #DrugDevelopment

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