EXTL2 and EXTL3 inhibition with siRNAs as a promising substrate reduction therapy for Sanfilippo C syndrome

Scientific Reports
Isaac CanalsDaniel Grinberg

Abstract

Sanfilippo syndrome is a rare lysosomal storage disorder caused by an impaired degradation of heparan sulfate (HS). It presents severe and progressive neurodegeneration and currently there is no effective treatment. Substrate reduction therapy (SRT) may be a useful option for neurological disorders of this kind, and several approaches have been tested to date. Here we use different siRNAs targeting EXTL2 and EXTL3 genes, which are important for HS synthesis, as SRT in Sanfilippo C patients' fibroblasts in order to decrease glycosaminoglycan (GAG) storage inside the lysosomes. The results show a high inhibition of the EXTL gene mRNAs (around 90%), a decrease in GAG synthesis after three days (30-60%) and a decrease in GAG storage after 14 days (up to 24%). Moreover, immunocytochemistry analyses showed a clear reversion of the phenotype after treatment. The in vitro inhibition of HS synthesis genes using siRNAs shown here is a first step in the development of a future therapeutic option for Sanfilippo C syndrome.

References

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Aug 20, 2009·European Journal of Human Genetics : EJHG·Xenia KaidonisSharon Byers
Jun 22, 2011·Cold Spring Harbor Perspectives in Biology·Stephane SarrazinJeffrey D Esko
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Citations

Jul 8, 2016·International Journal of Molecular Sciences·Maria Francisca CoutinhoSandra Alves
Nov 30, 2016·PloS One·Jasper J van GemstJohan van der Vlag
Apr 4, 2019·Journal of Inherited Metabolic Disease·Jenny Serra-VinardellDaniel Grinberg
Sep 19, 2020·Journal of Inherited Metabolic Disease·Berna Seker YilmazJulien Baruteau
Sep 19, 2017·Metabolic Brain Disease·Lidia GaffkeGrzegorz Węgrzyn
Sep 22, 2017·Diseases·Maria Francisca CoutinhoSandra Alves
Oct 28, 2020·International Journal of Molecular Sciences·Noelia BenetóIsaac Canals
Mar 29, 2019·Emerging Topics in Life Sciences·Wyatt W YueGustavo A Bezerra
Sep 20, 2020·European Journal of Pharmacology·Weijing KongYan Meng

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Methods Mentioned

BETA
transfection
PCR

Software Mentioned

Fiji
LightCycler® 480

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