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EXTL2 and EXTL3 inhibition with siRNAs as a promising substrate reduction therapy for Sanfilippo C syndrome
Canals Montferrer, Isaac; Benetó, Noelia; Cozar, Mónica; Vilageliu i Arqués, Lluïsa; Grinberg Vaisman, Daniel Raúl
Universitat de Barcelona
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.
Malalties hereditàries
Mutació (Biologia)
Genètica molecular humana
Malalties neurodegeneratives
Terapèutica
Genetic diseases
Mutation (Biology)
Human molecular genetics
Neurodegenerative Diseases
Therapeutics
cc-by-nc-nd (c) Canals Montferrer, Isaac et al., 2015
http://creativecommons.org/licenses/by-nc-nd/3.0/es
Artículo
info:eu-repo/semantics/publishedVersion
Nature Publishing Group
         

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