Remix Therapeutics™ Announces Publication in Science that Reveals Unprecedented Insights into Spliceosome Regulation and Alternative Splicing

WATERTOWN, Mass., Oct. 31, 2024 /PRNewswire/ -- Remix Therapeutics (Remix), a clinical-stage biotechnology company developing small molecule therapies to modulate RNA processing and address underlying drivers of disease, today announced the publication of a collaborative research study with Prof. Juan Valcárcel at the Center for Genomic Regulation in Barcelona, Spain in the prestigious journal Science.

The research article, titled "Transcriptome-wide splicing network reveals specialized regulatory functions of the core spliceosome," represents a significant advancement in understanding the complexities of RNA splicing regulation.

The study, conducted by the Valcárcel lab in collaboration with Remix Therapeutics, unveils distinct regulatory networks within the spliceosome and sheds light on how its intricate structural and conformational complexity modulates splice site selection. By knocking down the expression of 305 spliceosome components and regulators in human cancer cells and employing deep RNA sequencing, the researchers monitored over 250,000 alternative splicing events across all classes of splice site selection modes.

"This groundbreaking research provides mechanistic insights into the intricate workings of the spliceosome and its regulatory functions," said Dom Reynolds, CSO at Remix Therapeutics. "The findings not only advance our understanding of RNA processing but also open new avenues for therapeutic interventions in diseases associated with splicing dysregulation."

This collaborative effort led to several significant discoveries, including the unexpected finding that different protein components of the U1 snRNP complex, a well-studied ribonucleoprotein complex of the spliceosome, are differentially required for two classes of alternative splicing decisions, revealing an unprecedented division of labor in a core spliceosome component. This publication serves as a valuable resource for exploring targets of spliceosome components and associated regulatory factors, identifying modulators of alternative splicing events, and unraveling the complex regulatory relationships within one of the most intricate molecular machineries in eukaryotic cells.

"Our study uncovered complex networks within the spliceosome that control how genes are spliced. Unexpectedly, we found that different parts of a key spliceosome component, the U1 snRNP complex, have distinct roles in alternative splicing decisions.  The precise topological arrangement of snRNP complexes involved in spliceosome assembly occurring after initial splice site recognition, determines their activities in splice site selection, uncovering the extensive regulatory potential of this complex machinery" said Prof. Juan Valcárcel. "Our research with Remix substantially advances our understanding of the space and provides the foundation for leveraging RNA processing to develop novel therapeutics across a wide spectrum of human diseases."

The full article, "Transcriptome-wide splicing network reveals specialized regulatory functions of the core spliceosome" can be found here: https://www.science.org/doi/10.1126/science.adn8105#bibliography.

Additionally, Remix Therapeutics, in collaboration with Prof. Aaron Hoskins at the University of Wisconsin-Madison, recently published a mechanistic study on human U1 snRNP in Nature Communications. This publication sheds light on the binding mechanism of U1snRNP to 5'-splice sites and how small molecules can influence alternative splicing. The full article "A sequential binding mechanism for 5' splice site recognition and modulation for the human U1 snRNP" can be found here: https://www.nature.com/articles/s41467-024-53124-5.

About Remix Therapeutics
Remix Therapeutics is a clinical-stage biotechnology company developing novel small molecule therapies designed to reprogram RNA processing and treat disease. The REMaster™ technology platform facilitates RNA processing pattern identification, leveraging these learnings to modulate gene expression. Remix's innovative therapeutic approach has the potential to alter the way genes are read from the genome, to correct, enhance, or eliminate the gene message, thereby addressing disease drivers at their origin. For more information visit www.remixtx.com.

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SOURCE Remix Therapeutics