Targeting RNA splicing for disease therapy

Abstract

Splicing of pre-messenger RNA into mature messenger RNA is an essential step for expression of most genes in higher eukaryotes. Defects in this process typically affect cellular function and can have pathological consequences. Many human genetic diseases are caused by mutations that cause splicing defects. Furthermore, a number of diseases are associated with splicing defects that are not attributed to overt mutations. Targeting splicing directly to correct disease-associated aberrant splicing is a logical approach to therapy. Splicing is a favorable intervention point for disease therapeutics, because it is an early step in gene expression and does not alter the genome. Significant advances have been made in the development of approaches to manipulate splicing for therapy. Splicing can be manipulated with a number of tools including antisense oligonucleotides, modified small nuclear RNAs (snRNAs), trans-splicing, and small molecule compounds, all of which have been used to increase specific alternatively spliced isoforms or to correct aberrant gene expression resulting from gene mutations that alter splicing. Here we describe clinically relevant splicing defects in disease states, the current tools used to target and alter splicing, specific mutations and diseases that are being targeted using splice-modulating approaches, and emerging therapeutics.

Targeting the serrated pathway of colorectal cancer with mutation in BRAF

“…In general, aberrant splicing events may be therapeutically corrected by the overexpression or silencing of required splicing factors, by trans-splicing approaches (spliceosome-mediated trans-splicing between the endogenous transcript and a delivered cDNA copy), by using sequence-adapted U1 snRNAs (to promote or disturb exon recognition during spliceosome assembly), or by supplying short antisense oligonucleotides (ASOs) [168,169]. Of these, ASOs represent the most promising splice-modulating therapeutic strategy to correct overexpression of a splice variant such as RAC1b, because they hybridize to a selected site in the pre-mRNA, and sterically hinder its recognition by the spliceosomal machinery.…”

Insights on chiral, backbone modified peptide nucleic acids: Properties and biological activity

“…In this context, antisense oligonucleotides showed some promising results. 26 Pre-mRNA splicing into mature mRNA is an essential step for expression of most genes in higher eukaryotes. 27 Defects in this process typically affect cellular function and can have pathological consequences.…”

Functional analysis of splicing mutations in the IDS gene and the use of antisense oligonucleotides to exploit an alternative therapy for MPS II

“…Several studies have explored the potential of targeting aberrant premRNA resulting from splicing mutations. These include the use of small molecule compounds that modulate alternative splicing, the overexpression or silencing of splice factors, trans-splicing approaches (spliceosome-mediated RNA trans-splicing, SMaRT), use of adapted U1 snRNAs complementary to the mutated site and antisense oligonucleotides used to correct mutation-induced aberrant splicing (Spliceswitching oligonucleotides) or to redirect splicing to knock-down gene expression [12,13]. One of the most promising genetic therapies of this kind is pre-mRNA targeting by antisense oligonucleotides (AOs).…”