title: Efficacy of a combined intracerebral and systemic gene delivery approach for the treatment of a severe lysosomal storage disorder.
abstract: Multiple sulfatase deficiency (MSD), a severe autosomal recessive disease is caused by mutations in the sulfatase modifying factor 1 gene (Sumf1). We have previously shown that in the Sumf1 knockout mouse model (Sumf1(-/-)) sulfatase activities are completely absent and, similarly to MSD patients, this mouse model displays growth retardation and early mortality. The severity of the phenotype makes MSD unsuitable to be treated by enzyme replacement or bone marrow transplantation, hence the importance of testing the efficacy of novel treatment strategies. Here we show that recombinant adeno-associated virus serotype 9 (rAAV9) vector injected into the cerebral ventricles of neonatal mice resulted in efficient and widespread transduction of the brain parenchyma. In addition, we compared a combined, intracerebral ventricles and systemic, administration of an rAAV9 vector encoding SUMF1 gene to the single administrations-either directly in brain, or systemic alone -in MSD mice. The combined treatment resulted in the global activation of sulfatases, near-complete clearance of glycosaminoglycans (GAGs) and decrease of inflammation in both the central nervous system (CNS) and visceral organs. Furthermore, behavioral abilities were improved by the combined treatment. These results underscore that the "combined" mode of rAAV9 vector administration is an efficient option for the treatment of severe whole-body disorders.
authors.affiliation: Telethon Institute of Genetics and Medicine, Naples, Italy.
authors.forename: Carmine
authors.initials: C
authors.lastname: Spampanato
authors.forename: Elvira
authors.initials: E
authors.lastname: De Leonibus
authors.forename: Paola
authors.initials: P
authors.lastname: Dama
authors.forename: Annagiusi
authors.initials: A
authors.lastname: Gargiulo
authors.forename: Alessandro
authors.initials: A
authors.lastname: Fraldi
authors.forename: Nicolina Cristina
authors.initials: NC
authors.lastname: Sorrentino
authors.forename: Fabio
authors.initials: F
authors.lastname: Russo
authors.forename: Edoardo
authors.initials: E
authors.lastname: Nusco
authors.forename: Alberto
authors.initials: A
authors.lastname: Auricchio
authors.forename: Enrico M
authors.initials: EM
authors.lastname: Surace
authors.forename: Andrea
authors.initials: A
authors.lastname: Ballabio
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002490:Central Nervous System / Q000276:immunology / Q000473:pathology; D002552:Cerebral Ventricles / Q000821:virology; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D005455:Fluorescent Antibody Technique; D018014:Gene Transfer Techniques; D041722:Genes, Transgenic, Suicide; D015316:Genetic Therapy; D005822:Genetic Vectors; D006025:Glycosaminoglycans / Q000378:metabolism; D007249:Inflammation / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D052517:Multiple Sulfatase Deficiency Disease / Q000235:genetics* / Q000628:therapy*; D050862:Oxidoreductases Acting on Sulfur Group Donors; D013429:Sulfatases / Q000172:deficiency / Q000378:metabolism*
chemical_list: D006025:Glycosaminoglycans; D050862:Oxidoreductases Acting on Sulfur Group Donors; C519507:Sumf1 protein, mouse; D013429:Sulfatases