Toward gene therapy for gaucher disease

Donald B. Kohn, Jan Nolta, Joel Weinthal, Ingrid Bahner, Xiao Jin Yu, James Lilley, Gay M. Crooks

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

We are studying the transfer and expression by retroviral vectors of the human glucocerebrosidase (GC) gene into bone marrow cells as a model of gene therapy for genetic diseases of hematopoietic cells. A simple retroviral vector (G2) was developed that contains a normal human GC cDNA under the control of the Moloney murine leukemia virus long-terminal repeat (LTR) enhancer/promoter. Murine bone marrow was transduced with the G2 vector and maintained in long-term bone marrow culture (LTBMC). Expression of the human GC gene in the transduced murine LTBMC cells exceeded the level of endogenous murine GC mRNA. Murine bone marrow cells were also transduced with G2 and transplanted into irradiated syngeneic recipients. High levels of GC gene transfer and expression were seen in day-12 CFU-S foci, and to a lesser extent in the hematopoietic organs 4 months after gene transfer/bone marrow transplant (BMT). Human bone marrow, from a patient with Gaucher disease, was also used in studies of GC gene transduction. Gene transfer into 35-40% of the Gaucher hematopoietic progenitor cells was achieved, following prestimulation of the marrow with recombinant hematopoietic growth factors. Equal rates of gene transfer were obtained using either total marrow mononuclear cells or progenitor cells enriched 100-fold by immunomagnetic bead separation. GC gene transduction corrected the enzymatic deficiency of the Gaucher marrow. Our results demonstrate the potential utility of retroviral vector-mediated gene transfer for gene therapy of Gaucher disease. Current efforts are aimed at achieving more consistent in vivo GC expression in the murine BMT model and demonstrating transduction of pluripotent human hematopoietic stem cells. These technical challenges must be met if gene therapy using bone marrow stem cells is to be of likely clinical benefit.

Original languageEnglish (US)
Pages (from-to)101-105
Number of pages5
JournalHuman Gene Therapy
Volume2
Issue number2
StatePublished - 1991
Externally publishedYes

Fingerprint

Glucosylceramidase
Gaucher Disease
Genetic Therapy
Bone Marrow
Bone Marrow Cells
Genes
Hematopoietic Stem Cells
Stem Cells
Immunomagnetic Separation
Moloney murine leukemia virus
Transplants
Inborn Genetic Diseases
Terminal Repeat Sequences
Intercellular Signaling Peptides and Proteins
Complementary DNA
Gene Expression
Messenger RNA

ASJC Scopus subject areas

  • Genetics

Cite this

Kohn, D. B., Nolta, J., Weinthal, J., Bahner, I., Yu, X. J., Lilley, J., & Crooks, G. M. (1991). Toward gene therapy for gaucher disease. Human Gene Therapy, 2(2), 101-105.

Toward gene therapy for gaucher disease. / Kohn, Donald B.; Nolta, Jan; Weinthal, Joel; Bahner, Ingrid; Yu, Xiao Jin; Lilley, James; Crooks, Gay M.

In: Human Gene Therapy, Vol. 2, No. 2, 1991, p. 101-105.

Research output: Contribution to journalArticle

Kohn, DB, Nolta, J, Weinthal, J, Bahner, I, Yu, XJ, Lilley, J & Crooks, GM 1991, 'Toward gene therapy for gaucher disease', Human Gene Therapy, vol. 2, no. 2, pp. 101-105.
Kohn DB, Nolta J, Weinthal J, Bahner I, Yu XJ, Lilley J et al. Toward gene therapy for gaucher disease. Human Gene Therapy. 1991;2(2):101-105.
Kohn, Donald B. ; Nolta, Jan ; Weinthal, Joel ; Bahner, Ingrid ; Yu, Xiao Jin ; Lilley, James ; Crooks, Gay M. / Toward gene therapy for gaucher disease. In: Human Gene Therapy. 1991 ; Vol. 2, No. 2. pp. 101-105.
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