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Title: Splicing Modulation as a Promising Therapeutic Strategy for Lysosomal Storage Disorders: The Mucopolysaccharidoses Example
Authors: Santos, Juliana Inês
Gonçalves, Mariana
Matos, Liliana
Moreira, Luciana 
Carvalho, Sofia
Prata, Maria João 
Coutinho, Maria Francisca
Alves, Sandra
Keywords: lysosomal storage diseases (LSDs); mucopolysaccharidoses (MPSs); RNA-based therapies; antisense oligonucleotides (ASOs); splice-switching oligonucleotides (SSOs); U1 snRNA (small nuclear RNA)
Issue Date: 19-Apr-2022
Project: FCT/PTDC/BBBBMD/6301/2014 
FCT - EXPL/BTM-SAL/0659/2021 
Portuguese Society for Metabolic Disorders (Sociedade Portuguesa de Doenças Metabólicas, SPDM—Bolsa SPDM de apoio à investigação Dr Aguinaldo Cabral 2018 (2019DGH1629/SPDM2018I&D) and 2019 (2020DGH1834)), 
Sanfilippo Children’s Foundation (SCF Incubator Grant 2019: 2019DGH1656/SCF2019I&D) 
MPS Society (2019DGH1642) 
Serial title, monograph or event: Life
Volume: 12
Issue: 5
Abstract: Over recent decades, the many functions of RNA have become more evident. This molecule has been recognized not only as a carrier of genetic information, but also as a specific and essential regulator of gene expression. Different RNA species have been identified and novel and exciting roles have been unveiled. Quite remarkably, this explosion of novel RNA classes has increased the possibility for new therapeutic strategies that tap into RNA biology. Most of these drugs use nucleic acid analogues and take advantage of complementary base pairing to either mimic or antagonize the function of RNAs. Among the most successful RNA-based drugs are those that act at the pre-mRNA level to modulate or correct aberrant splicing patterns, which are caused by specific pathogenic variants. This approach is particularly tempting for monogenic disorders with associated splicing defects, especially when they are highly frequent among affected patients worldwide or within a specific population. With more than 600 mutations that cause disease affecting the pre-mRNA splicing process, we consider lysosomal storage diseases (LSDs) to be perfect candidates for this type of approach. Here, we introduce the overall rationale and general mechanisms of splicing modulation approaches and highlight the currently marketed formulations, which have been developed for non-lysosomal genetic disorders. We also extensively reviewed the existing preclinical studies on the potential of this sort of therapeutic strategy to recover aberrant splicing and increase enzyme activity in our diseases of interest: the LSDs. Special attention was paid to a particular subgroup of LSDs: the mucopolysaccharidoses (MPSs). By doing this, we hoped to unveil the unique therapeutic potential of the use of this sort of approach for LSDs as a whole.
ISSN: 2075-1729
DOI: 10.3390/life12050608
Rights: openAccess
Appears in Collections:FFUC- Artigos em Revistas Internacionais

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