Long-term enzyme correction and lipid reduction in multiple organs of primary and secondary transplanted Fabry mice receiving transduced bone marrow cells

Toshihiro Takenaka, Gary J. Murray, Gangjian Qin, Jane M. Quirk, Toshio Ohshima, Pankaj Qasba, Kelly Clark, Ashok B. Kulkarni, Roscoe O. Brady, Jeffrey A. Medin

Research output: Contribution to journalArticle

78 Citations (Scopus)

Abstract

Fabry disease is a compelling target for gene therapy as a treatment strategy. A deficiency in the lysosomal hydrolase α-galactosidase A (α-gal A; EC 3.2.1.22) leads to impaired catabolism of α-galactosyl-terminal lipids such as globotriaosylceramide (Gb3). Patients develop vascular occlusions that cause cardiovascular, cerebrovascular, and renal disease. Unlike for some lysosomal storage disorders, there is limited primary nervous system involvement in Fabry disease. The enzyme defect can be corrected by gene transfer. Overexpression of α-gal A by transduced cells results in secretion of this enzyme. Secreted enzyme is available for uptake by nontransduced cells presumably by receptor-mediated endocytosis. Correction of bystander cells may occur locally or systemically after circulation of the enzyme in the blood. In this paper we report studies on long-term genetic correction in an α-gal A-deficient mouse model of Fabry disease. α-gal A-deficient bone marrow mononuclear cells (BMMCs) were transduced with a retrovirus encoding α-gal A and transplanted into sublethally and lethally irradiated α-gal A- deficient mice. α-gal A activity and Gb3 levels were analyzed in plasma, peripheral blood mononuclear cells, BMMCs, liver, spleen, heart, lung, kidney, and brain. Primary recipient animals were followed for up to 26 weeks. BMMCs were then transplanted into secondary recipients. Increased α- gal A activity and decreased Gb3 storage were observed in all recipient groups in all organs and tissues except the brain. These effects occurred even with a low percentage of transduced cells. The findings indicate that genetic correction of bone marrow cells derived from patients with Fabry disease may have utility for phenotypic correction of patients with this disorder.

Original languageEnglish
Pages (from-to)7515-7520
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume97
Issue number13
DOIs
Publication statusPublished - 2000 Jun 20
Externally publishedYes

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Fabry Disease
Bone Marrow Cells
Lipids
Enzymes
Galactosidases
Kidney
Cerebrovascular Disorders
Brain
Hydrolases
Retroviridae
Endocytosis
Genetic Therapy
Nervous System
Blood Vessels
Blood Cells
Spleen
Lung
Liver
Genes

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Long-term enzyme correction and lipid reduction in multiple organs of primary and secondary transplanted Fabry mice receiving transduced bone marrow cells. / Takenaka, Toshihiro; Murray, Gary J.; Qin, Gangjian; Quirk, Jane M.; Ohshima, Toshio; Qasba, Pankaj; Clark, Kelly; Kulkarni, Ashok B.; Brady, Roscoe O.; Medin, Jeffrey A.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 97, No. 13, 20.06.2000, p. 7515-7520.

Research output: Contribution to journalArticle

Takenaka, Toshihiro ; Murray, Gary J. ; Qin, Gangjian ; Quirk, Jane M. ; Ohshima, Toshio ; Qasba, Pankaj ; Clark, Kelly ; Kulkarni, Ashok B. ; Brady, Roscoe O. ; Medin, Jeffrey A. / Long-term enzyme correction and lipid reduction in multiple organs of primary and secondary transplanted Fabry mice receiving transduced bone marrow cells. In: Proceedings of the National Academy of Sciences of the United States of America. 2000 ; Vol. 97, No. 13. pp. 7515-7520.
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AU - Medin, Jeffrey A.

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