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Diseases 2016, 4(4), 33; doi:10.3390/diseases4040033

Genetic Substrate Reduction Therapy: A Promising Approach for Lysosomal Storage Disorders

Research and Development Unit, Department of Human Genetics, INSA, National Health Institute Doutor Ricardo Jorge, Rua Alexandre Herculano, 321 4000-055 Porto, Portugal
These authors contributed equally to the work.
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Author to whom correspondence should be addressed.
Academic Editor: Jose A. Sanchez-Alcazar
Received: 30 September 2016 / Revised: 25 October 2016 / Accepted: 31 October 2016 / Published: 9 November 2016
(This article belongs to the Collection Lysosomal Storage Diseases)
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Abstract

Lysosomal storage diseases are a group of rare genetic disorders characterized by the accumulation of storage molecules in late endosomes/lysosomes. Most of them result from mutations in genes encoding for the catabolic enzymes that ensure intralysosomal digestion. Conventional therapeutic options include enzyme replacement therapy, an approach targeting the functional loss of the enzyme by injection of a recombinant one. Even though this is successful for some diseases, it is mostly effective for peripheral manifestations and has no impact on neuropathology. The development of alternative therapeutic approaches is, therefore, mandatory, and striking innovations including the clinical development of pharmacological chaperones and gene therapy are currently under evaluation. Most of them, however, have the same underlying rationale: an attempt to provide or enhance the activity of the missing enzyme to re-establish substrate metabolism to a level that is consistent with a lack of progression and/or return to health. Here, we will focus on the one approach which has a different underlying principle: substrate reduction therapy (SRT), whose uniqueness relies on the fact that it acts upstream of the enzymatic defect, decreasing storage by downregulating its biosynthetic pathway. Special attention will be given to the most recent advances in the field, introducing the concept of genetic SRT (gSRT), which is based on the use of RNA-degrading technologies (RNA interference and single stranded antisense oligonucleotides) to promote efficient substrate reduction by decreasing its synthesis rate. View Full-Text
Keywords: substrate reduction therapy (SRT); Gaucher disease (GD); mucopolysaccharidosis type III (MPS III; Sanfilippo syndrome); combination therapy substrate reduction therapy (SRT); Gaucher disease (GD); mucopolysaccharidosis type III (MPS III; Sanfilippo syndrome); combination therapy
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Coutinho, M.F.; Santos, J.I.; Matos, L.; Alves, S. Genetic Substrate Reduction Therapy: A Promising Approach for Lysosomal Storage Disorders. Diseases 2016, 4, 33.

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