Recombinant Encapsulated Cells Overexpressing Alpha-<i>L</i>-Iduronidase Correct Enzyme Deficiency in Human Mucopolysaccharidosis Type I Cells

Abstract

Mucopolysaccharidosis I (MPS I) is an autosomal recessive lysosomal storage disease due to deficient α-L-iduronidase (IDUA) activity. It results in the accumulation of the glycosaminoglycans (GAGs) heparan and dermatan sulfate and leads to several clinical manifestations. Available treatments are limited in their efficacy to treat some aspects of the disease. Thus, new approaches have been studied for the treatment of MPS I. Here, we tested the ability of recombinant baby hamster kidney cells transfected with human IDUA cDNA in correcting skin fibroblasts from MPS I patients in vitro. Our results showed an increase in IDUA activity in MPS I fibroblasts after 15, 30 and 45 days of coculture with the capsules. Cytological analysis showed a marked reduction in GAG storage within MPS I cells. Enzyme uptake by the fibroblasts was blocked in a dose-dependent manner with mannose-6-phosphate (M6P), indicating that cells use the M6P receptor to internalize the recombinant enzyme. Capsules were effective in correcting MPS I cells even after a 12-month period of cryopreservation. Taken together, our results indicate that cell encapsulation is a potential approach for treatment of MPS I. This approach becomes particularly interesting as a complementary approach, since the capsules could be implanted in sites which current treatments available are not able to reach. Future studies will focus on the efficacy of this approach in vivo.

Progressive eye pathology in mucopolysaccharidosis type I mice and effects of enzyme replacement therapy

“…Wild‐type littermates (WT, Idua −/+ and Idua +/+ ) and MPS I ( Idua −/− ) mice (donated by Elizabeth Neufeld, UCLA) with a C57BL/6 background were used in this study. Animals were genotyped at 21 days as previously described . Male and female WT and MPS I mice with two ( n = 4‐6), six ( n = 7‐12) and 8 months old ( n = 7‐6) were used.…”

Non Viral Gene Transfer Approaches for Lysosomal Storage Disorders

“…Cytological analysis showed a marked reduction in GAG storage within MPS I cells (Baldo et al, 2011). Ongoing experiments are under way in the MPS I mouse model.…”

Alginate-embedded HuH-7 cells increase MMP-9 and reduce OCLN expression in vitro

“…An interesting analysis would be to compare results at different times, plotting temporal changes in gene expression [21]. Studies have already shown the viability of encapsulated cells for longer culture periods, up to 45 days [30]. In order to improve the model, an increment in time culture could be carried out to asses if a longer period induces different expression of other markers.…”