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

研究成果: Article

78 引用 (Scopus)

抄録

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.

元の言語English
ページ(範囲)7515-7520
ページ数6
ジャーナルProceedings of the National Academy of Sciences of the United States of America
97
発行部数13
DOI
出版物ステータスPublished - 2000 6 20
外部発表Yes

Fingerprint

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

これを引用

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.

:: Proceedings of the National Academy of Sciences of the United States of America, 巻 97, 番号 13, 20.06.2000, p. 7515-7520.

研究成果: Article

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. :: Proceedings of the National Academy of Sciences of the United States of America. 2000 ; 巻 97, 番号 13. pp. 7515-7520.
@article{4780e70b6b45448bab69111b544ea0fc,
title = "Long-term enzyme correction and lipid reduction in multiple organs of primary and secondary transplanted Fabry mice receiving transduced bone marrow cells",
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.",
author = "Toshihiro Takenaka and Murray, {Gary J.} and Gangjian Qin and Quirk, {Jane M.} and Toshio Ohshima and Pankaj Qasba and Kelly Clark and Kulkarni, {Ashok B.} and Brady, {Roscoe O.} and Medin, {Jeffrey A.}",
year = "2000",
month = "6",
day = "20",
doi = "10.1073/pnas.120177997",
language = "English",
volume = "97",
pages = "7515--7520",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "13",

}

TY - JOUR

T1 - Long-term enzyme correction and lipid reduction in multiple organs of primary and secondary transplanted Fabry mice receiving transduced bone marrow cells

AU - Takenaka, Toshihiro

AU - Murray, Gary J.

AU - Qin, Gangjian

AU - Quirk, Jane M.

AU - Ohshima, Toshio

AU - Qasba, Pankaj

AU - Clark, Kelly

AU - Kulkarni, Ashok B.

AU - Brady, Roscoe O.

AU - Medin, Jeffrey A.

PY - 2000/6/20

Y1 - 2000/6/20

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=12944269059&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=12944269059&partnerID=8YFLogxK

U2 - 10.1073/pnas.120177997

DO - 10.1073/pnas.120177997

M3 - Article

C2 - 10840053

AN - SCOPUS:12944269059

VL - 97

SP - 7515

EP - 7520

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 13

ER -