2026-04-17T07:32:58Zhttps://recercat.cat/oai/request

oai:recercat.cat:2445/2094282025-11-20T13:51:10Zcom_2072_1057col_2072_478799col_2072_478917

00925njm 22002777a 4500 dc Bosch i Tubert, Fàtima author Haurigot, Virginia author Marcó, Sara author Ribera, Albert author García Martínez, Miguel author Ruzo, Albert author Villacampa, Pilar author Ayuso, Eduard author Añor Torres, Sònia author Andaluz Martínez, Anna author Pineda, Mercedes author García-Fructuoso, Gemma author Molas Laplana, Maria author Maggioni, Luca author Muñoz, Sergio author Motas, Sandra author Ruberte París, Jesús author Mingozzi, Federico author Pumarola i Batlle, Martí author 2024-04-05T17:56:30Z 2024-04-05T17:56:30Z 2013-07-01 2024-04-05T17:56:35Z 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. Lisosomes Teràpia genètica Líquid cefalorraquidi Lysosomes Gene therapy Cerebrospinal fluid Whole body correction of mucopolysaccharidosis IIIA by intracerebrospinal fluid gene therapy