RNA-Based Therapies for Inherited Metabolic Diseases

Abstract

In many genetic diseases for which there is to date no effective treatment, research in novel therapeutical targets and treatment options is one of the main objectives. In this context, many inherited metabolic diseases (IMD) fulfill the above criteria, and significant research is being performed in mutation-specific therapies. Specifically, a special attention has been given to splicing defects that account for 15–30% of the mutant alleles in most IMD. Splicing mutations are most commonly found at the conserved 3′ or 5′ splice sites at intron–exon junctions, but other types of changes have been described, including mutations affecting the polypyrimidine tract, exonic mutations affecting splice enhancers or silencers, and deep intronic mutations that activate or create splice sites resulting in the aberrant inclusion of pseudoexons in the mRNA. The understanding of the precise mechanisms leading to the splicing defect has paved the way for the implementation of splicing-directed RNA-based therapies. In IMD, several studies have explored the therapeutical potential of targeting the aberrant pre-mRNA resulting from splicing mutations, using overexpression or silencing of splicing factors and splice blocking antisense oligonucleotides. In this chapter, we review the existing knowledge on the splicing defects in IMD and their associated pathological effect as revealed by functional studies and the use of possible therapeutical interventions that can be applied to modulate splicing.