Retroviral-mediated transfer of the human glucocerebrosidase gene into cultured Gaucher bone marrow.

Nolta, Jan A.; Yu, Xiao; Bahner, Ingrid; Kohn, Donald B.

doi:10.1172/jci115868

Cited by 69 publications

(35 citation statements)

References 34 publications

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“…The enzyme deficiency of cultured skin fibroblasts and lymphoblasts from patients with Gaucher disease is readily corrected by retrovirusmediated transfer of the glucocerebrosidase cDNA (21,97,98). Efficient transfer of the cDNA into hematopoietic progenReview: Beutler itor stem cells is a more difficult task, but it has been achieved in murine (22-24, 99, 100) and to some extent in human (101) systems. In some cases, prolonged expression in macrophages of mice transplanted with transduced marrow cells has been documented (23,24).…”

Section: Genotype-phenotype Correlationsmentioning

confidence: 99%

Gaucher disease as a paradigm of current issues regarding single gene mutations of humans.

Beutler

1993

Proc. Natl. Acad. Sci. U.S.A.

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Gaucher disease is a glycolytic storage disease caused by a deficiency in activity of the catabolic enzyme glucocerebrosidase. Over 35 different mutations have been documented, including missense and nonsense point mutations, splicing mutations, deletions and insertions, a fusion gene, and examples of gene conversion. Gaucher disease is most common in the Ashkenazi Jewish population, in which just five of the mutations in this population account for 98% of the disease-producing alleles. Each of these mutations is found in the context of a single haplotype, a finding consistent with a single origin of each mutation. Although it is clear that these mutations provide a selective advantage in the Jewish population and thus constitute a balanced polymorphism, the nature of the advantage is unknown. Gaucher disease can be treated symptomatically, by administration of the missing enzyme, by allogeneic bone marrow transplantation, and potentially by gene transfer into hematopoietic stem cells. Increasing understanding of this disease has, as in other genetic disorders, created a host of social and ethical dilemmas regarding matters such as the cost of treatment for rare diseases and the advantages and disadvantages of population-targeted genetic screening.

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Section: Genotype-phenotype Correlationsmentioning

confidence: 99%

Gaucher disease as a paradigm of current issues regarding single gene mutations of humans.

Beutler

1993

Proc. Natl. Acad. Sci. U.S.A.

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“…This frequency of transfection is similar to the 10-40% transduction frequency obtained previously in human HSC using MLVbased retroviral vectors. 2,4,7,11,15,[29][30][31] However, the possible advantage of the nonviral procedure is that the small proportion of CD34 + cells that may represent the most primitive progenitors may be more amenable to transfection by nonviral methods that do not require cells to be actively cycling. Although extrapolation from transient CAT expression levels to long-term expression and cell survival cannot be taken for granted, this study suggests levels of gene transfer as determined by reporter gene activity correlated approximately with the ability to generate CFU-GM.…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies involving the transfection of CD34 + HPCs have mainly utilized murine leukemia virus (MLV)-derived retroviral vectors to transduce cells. Successful transfer and expression of various genes by these retroviral vectors into human bone marrow progenitors and long-term culture-initiating cells aimed at the eventual treatment of various diseases such as ADA deficiency, [1][2][3][4] X-linked granulomatous disease, 5 alpha-l-iduronidase deficiency (Hurler syndrome), 6 Gaucher's disease [7][8][9] and AIDS 10,11 Correspondence: GJ Nable, Howard have been reported. Other viral vectors based on the defective parvovirus, adeno-associated virus (AAV), [12][13][14] and an HIV-1 based retroviral vector pseudotyped with vesicular stomatitis virus envelope glycoprotein G 15 have also been used to produce stable gene transfer in hematopoietic cells.…”

Section: Introductionmentioning

confidence: 99%

Gene transfer into human umbilical cord blood-derived CD34+ cells by particle-mediated gene transfer

et al. 1998

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“…The human GC gene has been transduced into murine bone marrow stem cells and elevated levels of GC enzyme activity have been observed in mouse macrophages of long-term reconstituted mice (9)(10)(11). The GC gene has also been transduced into hematopoietic progenitor cells from bone marrow (12)(13)(14) and peripheral blood (15) of Gaucher patients, and the enzyme deficiency has been corrected in their progeny cells. Furthermore, primitive human hematopoietic cells that can repopulate immunocompromised BNX mice have been transduced with GC vectors (16).…”

mentioning

confidence: 99%

“…USA 92 (1995) been generated and used to transduce murine HSCs (29 (9,13). Alternatively, the 1.6-kbp GC cDNA (10,12) was used, creating a slightly shorter (but otherwise identical) LGEC vector.…”

mentioning

confidence: 99%

Selection of transduced CD34+ progenitors and enzymatic correction of cells from Gaucher patients, with bicistronic vectors.

Migita

Medin

Pawliuk

et al. 1995

Proc. Natl. Acad. Sci. U.S.A.

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The gene transfer efficiency of human hematopoietic stem cells is still inadequate for efficient gene therapy of most disorders. To overcome this problem, a selectable retroviral vector system for gene therapy has been developed for gene therapy of Gaucher disease. We constructed a bicistronic retroviral vector containing the human glucocerebrosidase (GC) cDNA and the human small cell surface antigen CD24 (243 bp). Expression of both cDNAs was controlled by the long terminal repeat enhancer/promoter of the Molony murine leukemia virus. The CD24 selectable marker was placed downstream of the GC cDNA and its translation was enhanced by inclusion of the long 5' untranslated region of encephalomyocarditis virus internal ribosomal entry site. Virus-producing GP+envAM12 cells were created by multiple supernatant transductions to create vector producer cells. The vector LGEC has a high titer and can drive expression of GC and the cell surface antigen CD24 simultaneously in transduced NIH 3T3 cells and Gaucher skin fibroblasts. These transduced cells have been successfully separated from untransduced cells by fluorescence-activated cell sorting, based on cell surface expression of CD24. Transduced and sorted NIH 3T3 cells showed higher GC enzyme activity than the unsorted population, demonstrating coordinated expression of both genes. Fibroblasts from Gaucher patients were transduced and sorted for CD24 expression, and GC enzyme activity was measured. The transduced sorted Gaucher fibroblasts had a marked increase in enzyme activity (149%) compared with virgin Gaucher fibroblasts (17% of normal GC enzyme activity). Efficient transduction of CD34+ hematopoietic progenitors (20-40%) was accomplished and fluorescence-activated cell sorted CD24+-expressing progenitors generated colonies, all of which (100%) were vector positive. The sorted, CD24-expressing progenitors generated erythroid burst-forming units, colony-forming units (CFU)-granulocyte, CFU-macrophage, CFU-granulocyte/macrophage, and CFU-mix hematopoietic colonies, demonstrating their ability to differentiate into these myeloid lineages in vitro. The transduced, sorted progenitors raised the GC enzyme levels in their progeny cells manyfold compared with untransduced CD34+ progenitors. Collectively, this demonstrates the development of high titer, selectable bicistronic vectors that allow isolation of transduced hematopoietic progenitors and cells that have been metabolically corrected.

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Retroviral-mediated transfer of the human glucocerebrosidase gene into cultured Gaucher bone marrow.

Abstract: Gaucher disease, a lysosomal glycolipid storage disorder, re-

Cited by 69 publications

References 34 publications

Gaucher disease as a paradigm of current issues regarding single gene mutations of humans.

Gaucher disease as a paradigm of current issues regarding single gene mutations of humans.

Gene transfer into human umbilical cord blood-derived CD34+ cells by particle-mediated gene transfer

Selection of transduced CD34+ progenitors and enzymatic correction of cells from Gaucher patients, with bicistronic vectors.

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