Projects per year
Abstract
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.
Original language | English |
---|---|
Pages (from-to) | 254-266 |
Number of pages | 13 |
Journal | Molecular Therapy |
Volume | 20 |
Issue number | 2 |
DOIs | |
Publication status | Published - 2012 |
Fingerprint
Dive into the research topics of 'Liver production of sulfamidase reverses peripheral and ameliorates CNS pathology in mucopolysaccharidosis IIIA mice'. Together they form a unique fingerprint.Projects
- 1 Finished
-
Estudi dels mecanismes responsables de la Retinopatia Diabètica i desenvolupament de noves aproximacions de teràpia gènica
Bosch Tubert, M. F. (Principal Investigator), Anguela Martínez, X. (Scholar), Jimenez, V. (Scholar), Villacampa Alcubierre, P. (Scholar), Barrero Victorio, J. (Investigator), Haurigot Mendoça, V. (Investigator), Mann , C. J. (Investigator), Molas Laplana, M. (Investigator) & Tafuro , S. (Investigator)
Institute of Health Carlos III (ISCIII)
18/10/06 → 30/12/09
Project: Research Projects and Other Grants