Uptake of alpha-(L)-iduronidase produced by retrovirally transduced fibroblasts into neuronal and glial cells in vitro.
Brown, O A
Morelli, A E
Fairbairn, Leslie J
Lashford, Linda S
Hatton, C E
Dexter, T Michael
Castro, M G
Lowenstein, P R
AffiliationDepartment of Medicine, University of Manchester School of Medicine, UK.
MetadataShow full item record
AbstractThe uptake of recombinant alpha-(L)-iduronidase into glial and neuronal cells, produced by retrovirally transduced NIH3T3 fibroblasts, was studied. We demonstrate that: (1) neuronal and glial cells take up alpha-(L)-iduronidase released into the medium by retrovirally transduced fibroblasts expressing high levels of alpha-(L)-iduronidase; (2) both glial and neuronal cells express the cation independent mannose-6-phosphate receptor responsible for lysosomal enzyme uptake; and (3) uptake of the lysosomal enzyme can be blocked by excess free mannose-6-phosphate, but not glucose-6-phosphate. Thus, various brain cells take up alpha-(L)-iduronidase, possibly through a cation independent mannose-6-phosphate receptor mediated pathway, and this uptake is higher in actively dividing or immature brain cells. Consequently, (1) neuronal metabolism ought to be capable of cross correction by enzyme provided by genetically engineered and transplanted cells provided by bone marrow transplantation (BMT); (2) that BMT could have a more beneficial effect on neurological function if performed as early as possible; and (3) given that the uptake mechanism of glial cells has a higher capacity, it might be easier to target diseases like the leukodystrophies in which lysosomal enzymes are needed in glial cells, compared to diseases where lysosomal enzymes ought to be delivered into neurons.
CitationUptake of alpha-(L)-iduronidase produced by retrovirally transduced fibroblasts into neuronal and glial cells in vitro. 1997, 4 (1):63-75 Gene Ther.
- Lipoprotein receptor binding, cellular uptake, and lysosomal delivery of fusions between the receptor-associated protein (RAP) and alpha-L-iduronidase or acid alpha-glucosidase.
- Authors: Prince WS, McCormick LM, Wendt DJ, Fitzpatrick PA, Schwartz KL, Aguilera AI, Koppaka V, Christianson TM, Vellard MC, Pavloff N, Lemontt JF, Qin M, Starr CM, Bu G, Zankel TC
- Issue date: 2004 Aug 13
- Retrovirus-mediated transfer of the human alpha-L-iduronidase cDNA into human hematopoietic progenitor cells leads to correction in trans of Hurler fibroblasts.
- Authors: Huang MM, Wong A, Yu X, Kakkis E, Kohn DB
- Issue date: 1997 Nov
- Uptake of a recombinant human alpha-L-iduronidase (laronidase) by cultured fibroblasts and osteoblasts.
- Authors: Tsukimura T, Tajima Y, Kawashima I, Fukushige T, Kanzaki T, Kanekura T, Ikekita M, Sugawara K, Suzuki T, Togawa T, Sakuraba H
- Issue date: 2008 Sep
- p-Isothiocyanatophenyl 6-phospho-alpha-D-mannopyranoside coupled to albumin. A model compound recognized by the fibroblast lysosomal enzyme uptake system. 2. Biological properties.
- Authors: Karson EM, Neufeld EF, Sando GN
- Issue date: 1980 Aug 5
- Overexpression of the human lysosomal enzyme alpha-L-iduronidase in Chinese hamster ovary cells.
- Authors: Kakkis ED, Matynia A, Jonas AJ, Neufeld EF
- Issue date: 1994 Jun