Splicing Modulation as a Promising Therapeutic Strategy for Lysosomal Storage Disorders: The Mucopolysaccharidoses Example
Abstract
:1. Introduction
2. Splicing: How It Works and How It Can Be Modulated
2.1. The Splicing Process: Machinery and Mechanisms
2.2. RNA-Based Approaches for Splice Modulation
2.3. Hurdles
3. Treatment Strategies for LSD Patients: MPSs in the Spotlight
3.1. Lysosomal Storage Diseases
3.2. Mucopolysaccharidoses
4. RNA-Based Therapeutic Approaches for MPS Mutations
4.1. Functional Studies of Splicing Mutations and Development of Therapeutic Approaches Using Antisense Oligonucleotides: The MPS II Example
4.2. Development of Therapeutic Approaches Using Modified U1 snRNA Vectors: The MPS IIIC Example
4.3. Identification and Characterization of Novel Splicing Defects and Assessment of Their Amenability for Splicing Correction Therapeutic Approaches: The MPS I Example
5. Challenges for the Development of Splice Modulation Approaches for MPSs
5.1. Existence of Disease-Relevant Models
5.2. Design and Development of Effective Delivery Strategies
5.3. Accurate Characterization of Disease-Causing Variants at mRNA Level
6. Concluding Remarks
Author Contributions
Funding
Institutional Review Board Statement
Data Availability Statement
Conflicts of Interest
References
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Brand Name | Drug | Year of Approval | Target Molecule | Treatment Result | Target Disease |
---|---|---|---|---|---|
Spinraza®, Biogen | Nusinersen | 2016 | SMN2 mRNA | Induces the inclusion of exon 7 in the SMN2 mRNA | Spinal muscular atrophy |
Exondys 51™, Sarepta Therapeutics | Eteplirsen | 2016 | Dystrophin mRNA | Induces the exclusion of exon 51 of dystrophin mRNA | Duchenne muscular dystrophy |
Vyondys 53™, Sarepta Therapeutics | Golodirsen | 2019 | Dystrophin mRNA | Induces the exclusion of exon 53 of dystrophin mRNA | Duchenne muscular dystrophy |
Viltepso®, NS Pharma | Viltolarsen | 2020 | Dystrophin mRNA | Induces the exclusion of exon 53 of dystrophin mRNA | Duchenne muscular dystrophy |
Amondys 45™, Sarepta Therapeutics | Casimersen | 2021 | Dystrophin mRNA | Induces the exclusion of exon 45 of dystrophin mRNA | Duchenne muscular dystrophy |
MPS Type | Common Name(s) | Associated Gene | Enzyme Deficiency | Number of Mutations | % of Splicing Mutations | Treatment Options Available |
---|---|---|---|---|---|---|
I | Hurler, Scheie and Hurler–Scheie syndromes | IDUA | Alpha-L-iduronidase | 320 | 15.3 | ERT, HSCT |
II | Hunter syndrome | IDS | Iduronate-2-sulfatase | 739 | 8.8 | ERT, HSCT |
IIIA | Sanfilippo syndrome type A | SGSH | Heparan-N-sulfatase | 163 | 2.5 | - |
IIIB | Sanfilippo syndrome type B | NAGLU | N-acetylglucosaminidase | 256 | 3.1 | - |
IIIC | Sanfilippo syndrome type C | HGSNAT | Acetyl CoA glucosamine N-acetyltransferase | 91 | 17.6 | - |
IIID | Sanfilippo syndrome type D | GNS | N-acetyl-glucosamine-6-sulfatase | 28 | 14.3 | - |
IVA | Morquio syndrome type A | GALNS | N-acetylgalactosamine-6-sulfate sulfatase | 378 | 10.3 | ERT, HSCT |
IVB | Morquio syndrome type B | GLB1 | β -galactosidase | 265 | 8.3 | - |
VI | Maroteaux–Lamy syndrome | ARSB | Arylsulfatase B | 229 | 5.7 | ERT |
VII | Sly syndrome | GUSB | β-glucuronidase | 81 | 7.4 | ERT |
IX | Hyaluronidasedeficiency | HYAL1 | Hyaluronidase | 7 | 0 | - |
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Santos, J.I.; Gonçalves, M.; Matos, L.; Moreira, L.; Carvalho, S.; Prata, M.J.; Coutinho, M.F.; Alves, S. Splicing Modulation as a Promising Therapeutic Strategy for Lysosomal Storage Disorders: The Mucopolysaccharidoses Example. Life 2022, 12, 608. https://doi.org/10.3390/life12050608
Santos JI, Gonçalves M, Matos L, Moreira L, Carvalho S, Prata MJ, Coutinho MF, Alves S. Splicing Modulation as a Promising Therapeutic Strategy for Lysosomal Storage Disorders: The Mucopolysaccharidoses Example. Life. 2022; 12(5):608. https://doi.org/10.3390/life12050608
Chicago/Turabian StyleSantos, Juliana Inês, Mariana Gonçalves, Liliana Matos, Luciana Moreira, Sofia Carvalho, Maria João Prata, Maria Francisca Coutinho, and Sandra Alves. 2022. "Splicing Modulation as a Promising Therapeutic Strategy for Lysosomal Storage Disorders: The Mucopolysaccharidoses Example" Life 12, no. 5: 608. https://doi.org/10.3390/life12050608