Therapeutic delivery of proteins to macrophages: implications for treatment of Gaucher's disease

Mistry, Pramod K.; Wraight, E. P.; Cox, Timothy M.

doi:10.1016/s0140-6736(96)04451-0

Cited by 90 publications

(47 citation statements)

References 26 publications

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“…This finding is not unexpected, because it has been demonstrated that the mannose receptor is also expressed on these cells (see Linehan et al 1999). Despite elegant studies with radiolabelled enzyme in volunteers, it remains an unanswered question, to which cells precisely mannose-terminated glucocerebrosidase is delivered in Gaucher patients (Mistry et al 1996). Further research on potential improvements in enzyme delivery to Gaucher cells in various body locations is required.…”

Section: Therapy Of Type 1 Gaucher Diseasementioning

confidence: 96%

Biochemistry of glycosphingolipid storage disorders: implications for therapeutic intervention

Aerts

Hollak

Boot

et al. 2003

Phil. Trans. R. Soc. Lond. B

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The physiological importance of the degradative processes in lysosomes is revealed by the existence of at least 40 distinct inherited diseases, the so-called lysosomal storage disorders. Most of these diseases are caused by a deficiency in a single lysosomal enzyme, or essential cofactor, and result in the lysosomal accumulation of one, or sometimes several, natural compounds. The most prevalent subgroup of the lysosomal storage disorders is formed by the sphingolipidoses, inherited disorders that are characterized by excessive accumulation of one or multiple (glyco)sphingolipids. The biology of glycosphingolipids has been extensively discussed in other contributions during this symposium. This review will therefore focus in depth on (type 1) Gaucher disease, a prototypical glycosphingolipidosis. The elucidation of the primary genetic defect, being a deficiency in the lysosomal glucocerebrosidase, is described. Characterization of glucocerebrosidase at protein and gene level has subsequently opened avenues for therapeutic intervention. The development of successful enzyme replacement therapy for type 1 Gaucher disease is discussed. Attention is also paid to the alternative approach of substrate modulation using orally administered inhibitors of glucosylceramide synthesis. Novel developments about the monitoring of age of onset, progression and correction of disease are described. The remaining challenges about pathophysiology of glycosphingolipidoses are discussed in view of further improvements in therapy for these debilitating disorders.

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Section: Therapy Of Type 1 Gaucher Diseasementioning

confidence: 96%

Biochemistry of glycosphingolipid storage disorders: implications for therapeutic intervention

Aerts

Hollak

Boot

et al. 2003

Phil. Trans. R. Soc. Lond. B

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“…The general experience is however that the skeletal response to therapy lags behind all other symptoms (7). In fact, although tissue distribution studies with tracer doses of radio-iodinated mannoseterminated enzyme show avid uptake in the marrow in proportion to the putative cellular pool of macrophages in this organ (8),direct ␤-glucosidase measurements in bone marrow aspirates showed very little activity of the infused enzyme in the marrow macrophages (9). Recent reports of studies in vitro point to the involvement of T lymphocytes in bone homeostasis via the regulation of osteoclast differentiation (10,11).…”

Section: Introductionmentioning

confidence: 99%

T Cell Numbers Relate to Bone Involvement in Gaucher Disease

Lacerda

Arosa

Lacerda

et al. 1999

Blood Cells, Molecules, and Diseases

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ABSTRACT:The major elements of bone pathology in Gaucher disease are a failure of osteoclast and osteoblast function, resulting in osteopenia and also osteonecrosis. T lymphocytes have recently been found to be involved in the regulation of osteoblast/osteoclast activity in vitro. In the present report the peripheral blood T major lymphocyte subsets were investigated in a group of genotyped type 1 Gaucher disease patients. A total of 31 patients were studied: 21 non-splenectomized (5 N370S homozygotes) and 10 splenectomized (of whom 1 was a N370S homozygote). The results show that non-splenectomized patients present a decrease in absolute numbers of peripheral blood T lymphocytes, specially the CD4 ϩ T subset. However, when patients were analyzed with respect to the presence of bone disease, the number of CD8 ϩ T lymphocytes was found to be statistically significantly lower in patients presenting bone involvement. Furthermore, lower numbers of CD8 ϩ T lymphocytes were significantly correlated with higher levels of plasma tartrate resistant acid phosphatase (TRAP) activity, a putative marker of osteoclast cell activity. These in vivo findings are in agreement with the results reached in vitro by others.

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“…The GC activities in livers of transduced mice were increased 3.4-and 1.9-fold via portal vein and tail vein injection, respectively. These up-leveled GC activities would certainly be effective [40]. The human GC enzyme expressed in this study did not have its oligosaccharide chain modified.…”

Section: Discussionmentioning

confidence: 93%

Expression and secretion of human glucocerebrosidase mediated by recombinant lentivirus vectors in vitro and in vivo: implications for gene therapy of Gaucher disease

Kim

Hong

Lai

et al. 2004

Biochemical and Biophysical Research Communications

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Therapeutic delivery of proteins to macrophages: implications for treatment of Gaucher's disease

Cited by 90 publications

References 26 publications

Biochemistry of glycosphingolipid storage disorders: implications for therapeutic intervention

Biochemistry of glycosphingolipid storage disorders: implications for therapeutic intervention

T Cell Numbers Relate to Bone Involvement in Gaucher Disease

Expression and secretion of human glucocerebrosidase mediated by recombinant lentivirus vectors in vitro and in vivo: implications for gene therapy of Gaucher disease

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