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2013-07-01

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Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/209428

Whole body correction of mucopolysaccharidosis IIIA by intracerebrospinal fluid gene therapy

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https://doi.org/10.1172/JCI66778

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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.

Matèries

Lisosomes, Teràpia genètica, Líquid cefalorraquidi

Matèries (anglès)

Lysosomes, Gene therapy, Cerebrospinal fluid

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Articles publicats en revistes (Ciències Fisiològiques)

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BOSCH I TUBERT, Fàtima, HAURIGOT, Virginia, MARCÓ, Sara, RIBERA, Albert, GARCÍA MARTÍNEZ, Miguel, RUZO, Albert, VILLACAMPA, Pilar, AYUSO, Eduard, AÑOR TORRES, Sònia, ANDALUZ MARTÍNEZ, Anna, PINEDA, Mercedes, GARCÍA-FRUCTUOSO, Gemma, MOLAS LAPLANA, Maria, MAGGIONI, Luca, MUÑOZ, Sergio, MOTAS, Sandra, RUBERTE PARÍS, Jesús, MINGOZZI, Federico, PUMAROLA I BATLLE, Martí. Whole body correction of mucopolysaccharidosis IIIA by intracerebrospinal fluid gene therapy. _Journal of Clinical Investigation_. 2013. Vol. 123, núm. 8, pàgs. 3254-3271. [consulta: 25 de gener de 2026]. ISSN: 0021-9738. [Disponible a: https://hdl.handle.net/2445/209428]

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