Abstract
Lysosomal storage disorders (LSDs) represent a group of more than 50 severe metabolic diseases caused by the deficiency of specific lysosomal hydrolases, activators, carriers, or lysosomal integral membrane proteins, leading to the abnormal accumulation of substrates within the lysosomes. Numerous mutations have been described in each disease-causing gene; among them, about 5–19% affect the pre-mRNA splicing process. In the last decade, several strategies to rescue/increase normal splicing of mutated transcripts have been developed and LSDs represent excellent candidates for this type of approach: (i) most of them are inherited in an autosomic recessive manner and patients affected by late-onset (LO) phenotypes often retain a fair amount of residual enzymatic activity; thus, even a small recovery of normal splicing may be beneficial in clinical settings; (ii) most LSDs still lack effective treatments or are currently treated with extremely expensive approaches; (iii) in few LSDs, a single splicing mutation accounts for up to 40–70% of pathogenic alleles. At present, numerous preclinical studies support the feasibility of reverting the pathological phenotype by partially rescuing splicing defects in LSDs. This review provides an overview of the impact of splicing mutations in LSDs and the related therapeutic approaches currently under investigation in these disorders.
Highlights
Lysosomal storage disorders (LSDs) are inherited metabolic disorders caused by a deficient function of specific lysosomal enzymes, activators, or integral membrane proteins, leading to an abnormal accumulation of incompletely degraded molecules within the lysosomes [1]
The splicing-therapy approaches mostly used up to now in this group of diseases have included the use of antisense oligonucleotide (AONs) and of modified U1 small nuclear RNAs (U1snRNA) that exploit base-pairing ability to target specific splicing regulatory sequences in the RNAs of interest
The field of RNA-based therapies has experienced remarkable progresses in the last few years, with many clinical trials being in an advanced state and the approval of the first antisense drugs becoming available to the market
Summary
Lysosomal storage disorders (LSDs) are inherited metabolic disorders caused by a deficient function of specific lysosomal enzymes, activators, or integral membrane proteins, leading to an abnormal accumulation of incompletely degraded molecules within the lysosomes [1]. Low levels of the specific enzyme/protein or the presence of a nonfunctional enzyme/protein within the lysosomal compartment cause the accumulation of undegraded substrate. They are all chronic multisystem conditions that present different phenotypes depending on the type of accumulated substrate, the site and the level of accumulation. Responsible genes and to develop novel therapeutic strategies To this date, numerous mutations have been described in each gene causing LSDs; among them, To this date, numerous mutations have been described in each gene causing LSDs; among about 5–19% affect the pre-mRNA splicing process [5]. This review aims to provide an overview the impact of splicing mutations in LSDs and the emerging therapeutic approaches based on RNA of the impact of splicing mutations in LSDs and the emerging therapeutic approaches based on RNA splicing currently under investigation in these disorders
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