Retroviral Vector-Mediated Transfer of the Galactocerebrosidase (GALC) cDNA Leads to Overexpression and Transfer of GALC Activity to Neighboring Cells

Rafi, Mohammad; Fugaro, Joseph M.; Amini, Shohreh; Luzi, Paola; de, Gregory; Victoria, Teresa; Dubell, Caren; Shahinfar, Maryam; Wenger, David A.

doi:10.1006/bmme.1996.0042

Cited by 41 publications

(26 citation statements)

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“…Also, while the enzyme is extremely hydrophobic and aggregates into a high molecular weight complex, it also may be taken up by neighboring cells by non-receptor-mediated mechanisms. Two recent studies have demonstrated retroviral gene correction of cells from GLD patients (Gama Sosa et al, 1996;Rafi et al, 1996b). Our studies using human GALC cDNA in a retroviral vector (MFG-GALC) have demonstrated that overexpression of GALC activity (100-200 times normal) in cultured skin fibroblasts is not toxic to cells 4 months after transduction and many doublings.…”

Section: Future Developmentsmentioning

confidence: 76%

“…This uptake of secreted enzyme by cells is inhibited less than 50% by mannose-6-phosphate indicating that the transfer is not solely via the mannose-6-phosphate receptor-mediated pathway. In addition to cultured fibroblasts, successful transduction of myoblasts, rat brain astrocytes, mouse Schwann cells, and human and canine hematopoietic cells has been demonstrated (Rafi et al, 1996b; Rafi MA, Luzi P, and Wenger DA, unpublished observations). Treatment of the human patients has been limited to bone marrow transplantation, and the results indicate that transplantation before serious neurological complications occur slows the progression of the disease (Shapiro et al, 1991).…”

Section: Future Developmentsmentioning

confidence: 98%

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Molecular genetics of Krabbe disease (globoid cell leukodystrophy): Diagnostic and clinical implications

1997

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Section: Future Developmentsmentioning

confidence: 76%

Section: Future Developmentsmentioning

confidence: 98%

Molecular genetics of Krabbe disease (globoid cell leukodystrophy): Diagnostic and clinical implications

1997

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“…The free enzyme binds to intracellular mannose 6-phosphate (Man-6-P) receptors, which deliver enzyme to the lysosomes. 17 Evidence for the transfer of excreted GALC from retrovirally transduced overexpression cells to fibroblasts of patients with Krabbe disease was reported previously 18 and this uptake was considered to partially involve Man-6-P receptors. Thus, when AxCAGALC was injected into the ventricle, the transgene product GALC might be secreted from the ependyma and spread to the surrounding brain parenchyma far beyond the ependymal layer of the detected LacZ-positive regions.…”

Section: Discussionmentioning

confidence: 87%

Intraventricular administration of recombinant adenovirus to neonatal twitcher mouse leads to clinicopathological improvements

Watabe

Ohashi

et al. 2001

Gene Ther

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Twitcher mouse is a murine model of human globoid cell leukodystrophy (Krabbe disease), which is characterized by a genetic deficiency in galactocerebrosidase (GALC) activity. The nervous system is affected early and severely by demyelination in the white matter. So far, there is no effective treatment for Krabbe disease except bone marrow transplantation (BMT). However, BMT has inherent limitations such as unavailability of donors and graft-versus-host disease. In this study, we injected recombinant adenovirus encoding GALC into the lateral ventricle of twitcher mice at postnatal day 0 (PND 0) and the therapeutic effects were evaluated. Our results showed slight, but significant

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“…Twitcher mice are being used to explore possible avenues for gene therapy. Highly promising results have been obtained in cell culture systems (52,53). The most commonly employed viral vectors are the retroviruses because of their well-characterized properties and their efficient and relatively nondiscriminatory capacity to infect various cell types.…”

Section: Examples Of Therapeutic Attemptsmentioning

confidence: 99%

Are animal models useful for understanding the pathophysiology of lysosomal storage disease?

et al. 2003

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Suzuki K, Ezoe T, Tohyama J, Matsuda J, Vanier MT, Suzuki K. Are animal models useful for understanding the pathophysiology of lysosomal storage disease? Acta Paediatr 2003; Suppl 443: 54-62. Stockholm. ISSN 0803-5326Spontaneously occurring genetic lysosomal storage diseases are as rare in other mammalian species as in man. However, the advent of gene targeting technology has revolutionized the state of animal models of genetic diseases. Nearly all lysosomal storage diseases known in man have been duplicated in the mouse. The technology now allows, not only complete inactivation of endogenous genes, but also the introduction of essentially any type of mutation. These animal models can overcome many of the limitations inherent in studies of human patients -rarity of the disease, extremely complex genetic background and logistical and ethical constraints in the design and execution of experiments with human subjects. For example, genetic manipulations of germ cells or cross-breeding experiments between two mutants are readily feasible with animal models. Two major areas of the utility of animal models are the clarification of the pathophysiology/ pathogenetic mechanism of disease and the exploration of therapeutic approaches. Examples of experiments using animal models of lysosomal storage disease are presented, primarily from studies undertaken in our own laboratory.Conclusion: Animal models have proved invaluable in extending our knowledge of the lysosomal storage diseases and exploring potential therapies.

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Retroviral Vector-Mediated Transfer of the Galactocerebrosidase (GALC) cDNA Leads to Overexpression and Transfer of GALC Activity to Neighboring Cells

Cited by 41 publications

References 0 publications

Molecular genetics of Krabbe disease (globoid cell leukodystrophy): Diagnostic and clinical implications

Molecular genetics of Krabbe disease (globoid cell leukodystrophy): Diagnostic and clinical implications

Intraventricular administration of recombinant adenovirus to neonatal twitcher mouse leads to clinicopathological improvements

Are animal models useful for understanding the pathophysiology of lysosomal storage disease?

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