More than a messenger: Alternative splicing as a therapeutic target

Area of Science:

• Molecular Biology
• Genetics
• RNA Biology

Background:

• Alternative splicing of pre-messenger RNA (mRNA) is a crucial post-transcriptional regulatory mechanism controlling gene expression.
• Aberrant alternative splicing due to genetic mutations is implicated in a wide range of severe human diseases.
• The intricate nature of splicing regulation offers diverse avenues for therapeutic intervention.

Purpose of the Study:

• To review recent therapeutic strategies for correcting disease-associated alternative splicing defects.
• To summarize genetic and chemical approaches targeting spliceosome components.
• To provide an overview of compounds targeting kinases and accessory pathways involved in splicing regulation.

Main Methods:

• Review of recent literature on therapeutic strategies for alternative splicing disorders.
• Analysis of splice-switching antisense oligonucleotides and small molecules targeting RNA.
• Summary of genetic and chemical approaches targeting spliceosome machinery.
• Overview of compounds targeting kinases and related pathways intersecting with splicing.

Main Results:

• Highlighting successful therapeutic strategies using splice-switching antisense oligonucleotides.
• Summarizing the efficacy of small molecules that bind directly to RNA for splicing modulation.
• Presenting various genetic and chemical methods to target spliceosome components for disease correction.
• Detailing compounds that modulate kinase and accessory pathways impacting splicing.

Conclusions:

• Advancements in understanding disease-specific splicing defects are driving the development of novel therapeutic options.
• Targeting alternative splicing represents a promising frontier for treating a spectrum of genetic disorders.
• The review consolidates current knowledge on therapeutic interventions for mis-regulated alternative splicing.