Whole body correction of mucopolysaccharidosis IIIA by intracerebrospinal fluid gene therapy

Marti Pumarola Batlle, Miguel Garcia Martinez, Luca Maggioni, Eduardo Ayuso Lopez, Jesus Ruberte Paris, Maria Fatima Bosch Tubert, Federico Mingozzi , Sonia Añor Torres, Ana Maria Andaluz Martinez, Sara Marcó, Virginia Haurigot, Albert Ribera, Albert Ruzo, Mercedes Pineda, Gemma García-Fructuoso, Pilar Villacampa, Maria Molas, Sergio Muñoz, Sandra Motas, Maria Fatima Bosch Tubert

Research output: Contribution to journalArticleResearchpeer-review

123 Citations (Scopus)

Abstract

For most lysosomal storage diseases (LSDs) affecting the CNS, there is currently no cure. The BBB, which limits the bioavailability of drugs administered systemically, and the short half-life of lysosomal enzymes, hamper the development of effective therapies. Mucopolysaccharidosis type IIIA (MPS IIIA) is an autosomic recessive LSD caused by a deficiency in sulfamidase, a sulfatase involved in the stepwise degradation of glycosaminoglycan (GAG) heparan sulfate. Here, we demonstrate that intracerebrospinal fluid (intra-CSF) administration of serotype 9 adenoassociated viral vectors (AAV9s) encoding sulfamidase corrects both CNS and somatic pathology in MPS IIIA mice. Following vector administration, enzymatic activity increased throughout the brain and in serum, leading to whole body correction of GAG accumulation and lysosomal pathology, normalization of behavioral deficits, and prolonged survival. To test this strategy in a larger animal, we treated beagle dogs using intracisternal or intracerebroventricular delivery. Administration of sulfamidase-encoding AAV9 resulted in transgenic expression throughout the CNS and liver and increased sulfamidase activity in CSF. High-titer serum antibodies against AAV9 only partially blocked CSF-mediated gene transfer to the brains of dogs. Consistently, anti-AAV antibody titers were lower in CSF than in serum collected from healthy and MPS IIIA-affected children. These results support the clinical translation of this approach for the treatment of MPS IIIA and other LSDs with CNS involvement.
Original languageEnglish
Pages (from-to)3254-3271
JournalJournal of Clinical Investigation
Volume123
DOIs
Publication statusPublished - 1 Aug 2013

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