Uptake of α-(L)-iduronidase produced by retrovirally transduced fibroblasts into neuronal and glial cells in vitro

Stewart, K; Brown, Oscar A.; Morelli, AE; Fairbairn, Leslie J.; Lashford, L. S.; Cooper, Alan; Hatton, C. E.; Dexter, T M; Castro, María G.; Pr, Lowenstein

doi:10.1038/sj.gt.3300364

Cited by 22 publications

(17 citation statements)

References 12 publications

(14 reference statements)

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“…This cross-correction was inhibited by mannose-6-phosphate but not by the structural analog glucose-6-phosphate, confirming that uptake was dependent on the mannose-6-phosphate receptor. 3 Thus, gene-corrected MPS-IH MSCs secrete IDUA in an appropriate form that may be taken up by non-gene-corrected cells.…”

Section: Resultsmentioning

confidence: 99%

“…This provides normal, enzyme-competent leukocytes that secrete IDUA that can be taken up by enzyme-deficient cells via mannose-6-phosphate receptors. 3 The utility of this approach is significantly limited by the availability of donors and significant toxicity of the intense immunosuppressive conditioning therapy that the recipient requires for donor hemopoiesis to become established without rejection. Even where donor hemopoiesis is fully established (ie, all hemopoietic cells have normal enzyme levels), symptoms (particularly defects in the skeleton and central nervous system) are incompletely and variably corrected.…”

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confidence: 99%

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Retrovirally mediated correction of bone marrow–derived mesenchymal stem cells from patients with mucopolysaccharidosis type I

Baxter

Wynn

Deakin

et al. 2002

Blood

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IntroductionMucopolysaccharidosis type IH (MPS-IH, Hurler syndrome) is an autosomal recessive disorder resulting from defects in the gene encoding the lysosomal enzyme ␣-L-iduronidase (IDUA). This leads to ineffective degradation of the glycosaminoglycans (GAGs) heparan sulfate and dermatan sulfate. Individuals with very low levels of IDUA present in infancy and early childhood as a consequence of the deleterious accumulation of these GAGs in different organ systems, including the central nervous system, reticuloendothelial system, and the skeleton. Such severely affected patients usually die within the first decade. 1,2 Current therapy for MPS-IH focuses on allogeneic bone marrow transplantation from an unaffected, HLA-compatible donor. This provides normal, enzyme-competent leukocytes that secrete IDUA that can be taken up by enzyme-deficient cells via mannose-6-phosphate receptors. 3 The utility of this approach is significantly limited by the availability of donors and significant toxicity of the intense immunosuppressive conditioning therapy that the recipient requires for donor hemopoiesis to become established without rejection. Even where donor hemopoiesis is fully established (ie, all hemopoietic cells have normal enzyme levels), symptoms (particularly defects in the skeleton and central nervous system) are incompletely and variably corrected. 4,5 Mesenchymal stem cells (MSCs) are multipotent progenitors that can be isolated from bone marrow and are capable of contributing to multiple mesenchymal tissues in vivo. [6][7][8][9][10] In this paper we demonstrate, for the first time, retroviral gene transfer leading to correction of these MSCs in an inherited disorder. Furthermore, there is maintenance of the proliferative and multilineage differentiation potential of these modified cells, and they are able to cross-correct non-gene-modified cells.Numerous studies have demonstrated the presence of donor mesenchymal cells in multiple tissues following transplantation, and MSCs injected into brain are able to differentiate into nerve cells. Taken with these, our data indicate that MSCs may prove a better target than hematopoietic stem cells in the context of gene therapy of multisystem, lysosomal storage disorders. Study design Isolation and culture of MSCsBone marrow samples were obtained from MPS-IH patients and unaffected individuals aged from 0 to 18 years, following informed parental consent and approval from the local research ethics committee. MSCs were isolated and cultured as previously described. 11 For differentiation assays, cells were plated at 5 ϫ 10 3 per well in 6-well plates in growth medium with either osteogenic 12 or adipogenic 13 supplements. For differentiation along the neuronal lineage, cells were preincubated for 24 hours in Dulbecco modified Eagle medium/20% fetal calf serum/1 mM ␤-mercapotethanol and then switched into Dulbecco modified Eagle medium/5 mM ␤-mercapotethanol. 14 Mineralized bone was stained by the von Kossa technique, 15 and adipocytes were stained using oil-red-O. 16 N...

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Retrovirally mediated correction of bone marrow–derived mesenchymal stem cells from patients with mucopolysaccharidosis type I

Baxter

Wynn

Deakin

et al. 2002

Blood

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“…Except for some tumor-derived cell lines mannose 6-phosphate receptors have been detected in all cell types including neurons, astrocytes and oligodendrocytes, and mannose 6-phosphate-dependent endocytosis of lysosomal enzymes has been demonstrated for both glial and neuronal cells. 7,8 The metabolic cross-correction of cultured cells and the ubiquituous expression of mannose 6-phosphate receptors favored efforts to establish clinically applicable methods for efficient substitution of the missing enzyme in patients. Repetitive intravenous injection of the deficient enzyme was found to be of therapeutic benefit only in some lysosomal storage diseases without central nervous system (CNS) involvement.…”

Section: Introductionmentioning

confidence: 99%

Bone marrow stem cell-based gene transfer in a mouse model for metachromatic leukodystrophy: effects on visceral and nervous system disease manifestations

et al. 2002

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“…To evaluate the frequency of hASA-expressing BM progenitor cells 1.5 ml methylcellulose medium, supplemented with 10 ng/ml IL-3, 10 ng/ml IL-6, 50 ng/ml SCF and 3 U/ml erythropoietin (StemCell Technologies, Vancouver, Canada) was mixed with 1 × 10 4 BMCs and incubated at 37°C. After 2 weeks individual colonies (Ͼ100 cells) were extracted, lysed in 30 l 1 × TBS pH 7.4, 0.5% Triton X-100 and 3 l of each sample was assayed for hASA by ELISA.…”

Section: Clonogenic Assays Of Bm Progenitor Cellsmentioning

confidence: 99%

“…2 These include the ubiquitous expression of the mannose 6-phosphate/insulin-like growth factor II receptor which internalizes extracellular lysosomal enzymes including ASA. 3,4 Exogenous enzymes are delivered to the lysosome and can cross-correct the metabolic defect of enzyme-deficient cells. 5 Due to the targeting function of the receptor, a sustained supply of the central nervous system (CNS) with ASA can be expected to result in a beneficial effect on the disease.…”

Section: Introductionmentioning

confidence: 99%

Long-term expression and transfer of arylsulfatase A into brain of arylsulfatase A-deficient mice transplanted with bone marrow expressing the arylsulfatase A cDNA from a retroviral vector

et al. 2000

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Uptake of α-(L)-iduronidase produced by retrovirally transduced fibroblasts into neuronal and glial cells in vitro

Cited by 22 publications

References 12 publications

Retrovirally mediated correction of bone marrow–derived mesenchymal stem cells from patients with mucopolysaccharidosis type I

Retrovirally mediated correction of bone marrow–derived mesenchymal stem cells from patients with mucopolysaccharidosis type I

Bone marrow stem cell-based gene transfer in a mouse model for metachromatic leukodystrophy: effects on visceral and nervous system disease manifestations

Long-term expression and transfer of arylsulfatase A into brain of arylsulfatase A-deficient mice transplanted with bone marrow expressing the arylsulfatase A cDNA from a retroviral vector

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