Reduction of GAG storage in MPS II mouse model following implantation of encapsulated recombinant myoblasts.
BACKGROUND
Hunter syndrome, mucopolysaccharidosis type II (MPS II), is a X-linked inherited disorder caused by the deficiency of the enzyme iduronate-2-sulfatase (IDS), involved in the lysosomal catabolism of the glycosaminoglycans (GAG) dermatan and heparan sulfate. Such a deficiency leads to the intracellular accumulation of undegraded GAG and eventually to a progressive severe clinical pattern. Many attempts have been made in the last two to three decades to identify possible therapeutic strategies for the disorder, including gene therapy and somatic cell therapy.


METHODS
In this study we evaluated the intraperitoneal implantation of allogeneic myoblasts over-expressing IDS, enclosed in alginate microcapsules, in the MPS II mouse model. Animals were monitored for 8 weeks post-implantation, during which plasma and tissue IDS levels, as well as tissue and urinary GAG contents, were measured.


CONCLUSIONS
Induced enzyme activity occurred both in the plasma and in the different tissues analyzed. A significant decrease in urinary undegraded GAG between the fourth and the sixth week of treatment was observed. Moreover, a biochemical reduction of GAG deposits was measured 8 weeks after treatment in the liver and kidney, on average 30 and 38%, respectively, while in the spleen GAG levels were almost normalized. Finally, the therapeutic effect was confirmed by histolochemical examination of the same tissues. Such effects were obtained following implantation of about 1.5 x 10(6) recombinant cells/animal. Taken together, these results represent a clear evidence of the therapeutic efficacy of this strategy in the MPS II mouse model, and encourage further evaluation of this approach for potential treatment of human beings.
Friso
Adelaide
A
Gene Therapy Laboratory, Centre for Rare Diseases and Department of Pediatrics, University of Padova, Italy.
Tomanin
Rosella
R
Alba
Sabrina
S
Gasparotto
Nicoletta
N
Puicher
Elisabetta Piller
EP
Fusco
Mariella
M
Hortelano
Gonzalo
G
Muenzer
Joseph
J
Marin
Oriano
O
Zacchello
Franco
F
Scarpa
Maurizio
M
D000818:Animals; D002214:Capsules; D017690:Cell Transplantation / Q000379:methods*; D004195:Disease Models, Animal; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism*; D006025:Glycosaminoglycans / Q000378:metabolism*; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016532:Mucopolysaccharidosis II / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy; D032446:Myoblasts / Q000166:cytology / Q000502:physiology*; D013154:Spleen / Q000166:cytology / Q000378:metabolism
D002214:Capsules; D006023:Glycoproteins; D006025:Glycosaminoglycans; C018322:IDS protein, human