Disease correction by AAV-mediated gene therapy in a new mouse model of mucopolysaccharidosis type IIID

Carles Roca, Sandra Motas, Sara Marco, Albert Ribera, Victor Sanchez, Xavier Sanchez, Joan Bertolin, Xavier Leon, Jennifer Perez, Miguel Garcia, Pilar Villacampa, Jesus Ruberte, Anna Pujol, Virginia Haurigot, Fatima Bosch

Research output: Contribution to journalArticleResearchpeer-review

32 Citations (Scopus)


© The Author 2017. Published by Oxford University Press. All rights reserved. Gene therapy is a promising therapeutic alternative for Lysosomal Storage Disorders (LSD), as it is not necessary to correct the genetic defect in all cells of an organ to achieve therapeutically significant levels of enzyme in body fluids, from which nontransduced cells can uptake the protein correcting their enzymatic deficiency. Animalmodels are instrumental in the development of new treatments for LSD. Here we report the generation of the firstmousemodel of the LSD Muccopolysaccharidosis Type IIID (MPSIIID), also known as Sanfilippo syndrome type D. This autosomic recessive, heparan sulphate storage disease is caused by deficiency in N-acetylglucosamine 6-sulfatase (GNS). Mice deficient in GNS showed lysosomal storage pathology and loss of lysosomal homeostasis in the CNS and peripheral tissues, chronic widespread neuroinflammation, reduced locomotor and exploratory activity and shortened lifespan, a phenotype that closely resembled human MPSIIID. Moreover, treatment of the GNS-deficient animals with GNS-encoding adeno-associated viral (AAV) vectors of serotype 9 delivered to the cerebrospinal fluid completely corrected pathological storage, improved lysosomal functionality in the CNS and somatic tissues, resolved neuroinflammation, restored normal behaviour and extended lifespan of treatedmice. Hence, this work represents the first step towards the development of a treatment for MPSIIID.
Original languageEnglish
Article numberddx058
Pages (from-to)1535-1551
JournalHuman Molecular Genetics
Issue number8
Publication statusPublished - 15 Apr 2017


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