Liver production of sulfamidase reverses peripheral and ameliorates CNS pathology in mucopolysaccharidosis IIIA mice.
Mucopolysaccharidosis type IIIA (MPSIIIA) is an inherited lysosomal storage disease caused by deficiency of sulfamidase, resulting in accumulation of the glycosaminoglycan (GAG) heparan sulfate. It is characterized by severe progressive neurodegeneration, together with somatic alterations, which lead to death during adolescence. Here, we tested the ability of adeno-associated virus (AAV) vector-mediated genetic modification of either skeletal muscle or liver to revert the already established disease phenotype of 2-month-old MPSIIIA males and females. Intramuscular administration of AAV-Sulfamidase failed to achieve significant therapeutic benefit in either gender. In contrast, AAV8-mediated liver-directed gene transfer achieved high and sustained levels of circulating active sulfamidase, which reached normal levels in females and was fourfold higher in males, and completely corrected lysosomal GAG accumulation in most somatic tissues. Remarkably, a 50% reduction of GAG accumulation was achieved throughout the entire brain of males, which correlated with a partial improvement of the pathology of cerebellum and cortex. Liver-directed gene transfer expanded the lifespan of MPSIIIA males, underscoring the importance of reaching supraphysiological plasma levels of enzyme for maximal therapeutic benefit. These results show how liver-directed gene transfer can reverse somatic and ameliorate neurological pathology in MPSIIIA.
Center of Animal Biotechnology and Gene Therapy, School of Veterinary Medicine, Universitat Autònoma de Barcelona, Bellaterra, Spain.
Albert
A
Ruzo
Miquel
M
Garcia
Albert
A
Ribera
Pilar
P
Villacampa
Virginia
V
Haurigot
Sara
S
Marcó
Eduard
E
Ayuso
Xavier M
XM
Anguela
Carles
C
Roca
Judith
J
Agudo
David
D
Ramos
Jesús
J
Ruberte
Fatima
F
Bosch
D000818:Animals; D002490:Central Nervous System / Q000473:pathology*; D002531:Cerebellum / Q000648:ultrastructure; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D023061:Gene Order; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics / Q000493:pharmacokinetics; D006867:Hydrolases / Q000235:genetics* / Q000378:metabolism; D007273:Injections, Intramuscular; D007275:Injections, Intravenous; D008099:Liver / Q000378:metabolism* / Q000648:ultrastructure; D008247:Lysosomes / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009084:Mucopolysaccharidosis III / Q000235:genetics / Q000401:mortality / Q000628:therapy*; D018482:Muscle, Skeletal / Q000378:metabolism; D016019:Survival Analysis; D014161:Transduction, Genetic; D014793:Visual Cortex / Q000473:pathology / Q000648:ultrastructure
D006867:Hydrolases; C022708:N-sulfoglucosamine sulfohydrolase