title: Biochemical, histological and functional correction of mucopolysaccharidosis type IIIB by intra-cerebrospinal fluid gene therapy.
abstract: Gene therapy is an attractive tool for the treatment of monogenic disorders, in particular for lysosomal storage diseases (LSD) caused by deficiencies in secretable lysosomal enzymes in which neither full restoration of normal enzymatic activity nor transduction of all affected cells are necessary. However, some LSD such as Mucopolysaccharidosis Type IIIB (MPSIIIB) are challenging because the disease's main target organ is the brain and enzymes do not efficiently cross the blood-brain barrier even if present at very high concentration in circulation. To overcome these limitations, we delivered AAV9 vectors encoding for α-N-acetylglucosaminidase (NAGLU) to the Cerebrospinal Fluid (CSF) of MPSIIIB mice with the disease already detectable at biochemical, histological and functional level. Restoration of enzymatic activity in Central Nervous System (CNS) resulted in normalization of glycosaminoglycan content and lysosomal physiology, resolved neuroinflammation and restored the pattern of gene expression in brain similar to that of healthy animals. Additionally, transduction of the liver due to passage of vectors to the circulation led to whole-body disease correction. Treated animals also showed reversal of behavioural deficits and extended lifespan. Importantly, when the levels of enzymatic activity were monitored in the CSF of dogs following administration of canine NAGLU-coding vectors to animals that were either naïve or had pre-existing immunity against AAV9, similar levels of activity were achieved, suggesting that CNS efficacy would not be compromised in patients seropositive for AAV9. Our studies provide a strong rationale for the clinical development of this novel therapeutic approach as the treatment for MPSIIIB.
authors.affiliation: Center of Animal Biotechnology and Gene Therapy, Department of Biochemistry and Molecular Biology.
authors.forename: Albert
authors.initials: A
authors.lastname: Ribera
authors.affiliation: Center of Animal Biotechnology and Gene Therapy, Department of Biochemistry and Molecular Biology.
authors.forename: Virginia
authors.initials: V
authors.lastname: Haurigot
authors.affiliation: Center of Animal Biotechnology and Gene Therapy, Department of Biochemistry and Molecular Biology.
authors.forename: Miguel
authors.initials: M
authors.lastname: Garcia
authors.affiliation: Center of Animal Biotechnology and Gene Therapy, Department of Biochemistry and Molecular Biology.
authors.forename: Sara
authors.initials: S
authors.lastname: Marcó
authors.affiliation: Center of Animal Biotechnology and Gene Therapy, Department of Biochemistry and Molecular Biology.
authors.forename: Sandra
authors.initials: S
authors.lastname: Motas
authors.affiliation: Center of Animal Biotechnology and Gene Therapy, Department of Biochemistry and Molecular Biology.
authors.forename: Pilar
authors.initials: P
authors.lastname: Villacampa
authors.affiliation: Center of Animal Biotechnology and Gene Therapy, Department of Biochemistry and Molecular Biology.
authors.forename: Luca
authors.initials: L
authors.lastname: Maggioni
authors.affiliation: Center of Animal Biotechnology and Gene Therapy, Department of Biochemistry and Molecular Biology.
authors.forename: Xavier
authors.initials: X
authors.lastname: León
authors.affiliation: Center of Animal Biotechnology and Gene Therapy, Department of Biochemistry and Molecular Biology.
authors.forename: Maria
authors.initials: M
authors.lastname: Molas
authors.affiliation: Center of Animal Biotechnology and Gene Therapy, Department of Biochemistry and Molecular Biology.
authors.forename: Víctor
authors.initials: V
authors.lastname: Sánchez
authors.affiliation: Center of Animal Biotechnology and Gene Therapy, Department of Biochemistry and Molecular Biology.
authors.forename: Sergio
authors.initials: S
authors.lastname: Muñoz
authors.affiliation: Généthon, 91000 Evry, France and.
authors.forename: Christian
authors.initials: C
authors.lastname: Leborgne
authors.affiliation: Department of Animal Medicine and Surgery and.
authors.forename: Xavier
authors.initials: X
authors.lastname: Moll
authors.affiliation: Center of Animal Biotechnology and Gene Therapy, Department of Animal Medicine and Surgery and.
authors.forename: Martí
authors.initials: M
authors.lastname: Pumarola
authors.affiliation: Généthon, 91000 Evry, France and University Pierre and Marie Curie, 75005 Paris, France.
authors.forename: Federico
authors.initials: F
authors.lastname: Mingozzi
authors.affiliation: Center of Animal Biotechnology and Gene Therapy, Department of Animal Health and Anatomy, School of Veterinary Medicine, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain.
authors.forename: Jesús
authors.initials: J
authors.lastname: Ruberte
authors.affiliation: Department of Animal Medicine and Surgery and.
authors.forename: Sònia
authors.initials: S
authors.lastname: Añor
authors.affiliation: Center of Animal Biotechnology and Gene Therapy, Department of Biochemistry and Molecular Biology, fatima.bosch@uab.es.
authors.forename: Fatima
authors.initials: F
authors.lastname: Bosch
mesh_terms: D000118:Acetylglucosaminidase / Q000134:cerebrospinal fluid / Q000235:genetics*; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D000229:Dependovirus / Q000235:genetics / Q000378:metabolism; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009084:Mucopolysaccharidosis III / Q000134:cerebrospinal fluid / Q000201:enzymology / Q000235:genetics* / Q000628:therapy*
chemical_list: C033079:alpha-N-acetyl-D-glucosaminidase; D000118:Acetylglucosaminidase