Bone marrow gene transfer in three patients with adenosine deaminase deficiency

P M Hoogerbrugge, V W van Beusechem, A Fischer, M Debree, F le Deist, J L Perignon, G Morgan, B Gaspar, L D Fairbanks, C H Skeoch, A Moseley, M Harvey, R J Levinsky, D Valerio

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Adenosine deaminase (ADA) deficiency results in severe combined immune deficiency disease (SCID), which is fatal without treatment. Allogeneic bone marrow transplantation (BMT) is the treatment of choice if an HLA-identical sibling bone marrow donor is available, resulting in almost 100% cure rate. BMT-related mortality is high in patients lacking such a donor. For these patients, efficient transfer of a recombinant ADA gene into hematopoietic stem cells is a therapeutic option if it results in the outgrowth of a 'genetically repaired' lymphoid system. Based on successful gene transfer studies in monkeys, we performed retrovirus-mediated gene transfer into CD34+ bone marrow cells of three patients with ADA deficiency. Two patients received bovine ADA conjugated to polyethylene glycol (PEG-ADA); in the third patient, PEG-ADA was started 4 months after gene transfer. Gene transfer resulted in a 5-12% transduction frequency of in vitro colony forming cells (CFU-Cs). No toxicity was observed during and after infusion of the graft. Following infusion of the transduced CD34+ cells, transduced granulocytes and mononuclear cells persisted in the circulation for 3 months. In addition, the gene was present in the marrow of one of the patients at 6 months after gene transfer. Expression of the gene was not detected. After this period, the gene could not be detected. In monkey studies we showed that myeloablation, which was not performed in the patients, may enhance engraftment of genetically modified cells. We hypothesize that lack of myeloablation, administration of bovine ADA and low numbers of transduced progenitor cells all may have contributed to the relative low numbers of transduced cells in the patients. Under these conditions, no selective advantage of the genetically corrected progenitor cells was observed.

Original languageEnglish
Pages (from-to)179-83
Number of pages5
JournalGene Therapy
Volume3
Issue number2
Publication statusPublished - Feb 1996

Cite this

Hoogerbrugge, P. M., van Beusechem, V. W., Fischer, A., Debree, M., le Deist, F., Perignon, J. L., ... Valerio, D. (1996). Bone marrow gene transfer in three patients with adenosine deaminase deficiency. Gene Therapy, 3(2), 179-83.
Hoogerbrugge, P M ; van Beusechem, V W ; Fischer, A ; Debree, M ; le Deist, F ; Perignon, J L ; Morgan, G ; Gaspar, B ; Fairbanks, L D ; Skeoch, C H ; Moseley, A ; Harvey, M ; Levinsky, R J ; Valerio, D. / Bone marrow gene transfer in three patients with adenosine deaminase deficiency. In: Gene Therapy. 1996 ; Vol. 3, No. 2. pp. 179-83.
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title = "Bone marrow gene transfer in three patients with adenosine deaminase deficiency",
abstract = "Adenosine deaminase (ADA) deficiency results in severe combined immune deficiency disease (SCID), which is fatal without treatment. Allogeneic bone marrow transplantation (BMT) is the treatment of choice if an HLA-identical sibling bone marrow donor is available, resulting in almost 100{\%} cure rate. BMT-related mortality is high in patients lacking such a donor. For these patients, efficient transfer of a recombinant ADA gene into hematopoietic stem cells is a therapeutic option if it results in the outgrowth of a 'genetically repaired' lymphoid system. Based on successful gene transfer studies in monkeys, we performed retrovirus-mediated gene transfer into CD34+ bone marrow cells of three patients with ADA deficiency. Two patients received bovine ADA conjugated to polyethylene glycol (PEG-ADA); in the third patient, PEG-ADA was started 4 months after gene transfer. Gene transfer resulted in a 5-12{\%} transduction frequency of in vitro colony forming cells (CFU-Cs). No toxicity was observed during and after infusion of the graft. Following infusion of the transduced CD34+ cells, transduced granulocytes and mononuclear cells persisted in the circulation for 3 months. In addition, the gene was present in the marrow of one of the patients at 6 months after gene transfer. Expression of the gene was not detected. After this period, the gene could not be detected. In monkey studies we showed that myeloablation, which was not performed in the patients, may enhance engraftment of genetically modified cells. We hypothesize that lack of myeloablation, administration of bovine ADA and low numbers of transduced progenitor cells all may have contributed to the relative low numbers of transduced cells in the patients. Under these conditions, no selective advantage of the genetically corrected progenitor cells was observed.",
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author = "Hoogerbrugge, {P M} and {van Beusechem}, {V W} and A Fischer and M Debree and {le Deist}, F and Perignon, {J L} and G Morgan and B Gaspar and Fairbanks, {L D} and Skeoch, {C H} and A Moseley and M Harvey and Levinsky, {R J} and D Valerio",
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Hoogerbrugge, PM, van Beusechem, VW, Fischer, A, Debree, M, le Deist, F, Perignon, JL, Morgan, G, Gaspar, B, Fairbanks, LD, Skeoch, CH, Moseley, A, Harvey, M, Levinsky, RJ & Valerio, D 1996, 'Bone marrow gene transfer in three patients with adenosine deaminase deficiency' Gene Therapy, vol. 3, no. 2, pp. 179-83.

Bone marrow gene transfer in three patients with adenosine deaminase deficiency. / Hoogerbrugge, P M; van Beusechem, V W; Fischer, A; Debree, M; le Deist, F; Perignon, J L; Morgan, G; Gaspar, B; Fairbanks, L D; Skeoch, C H; Moseley, A; Harvey, M; Levinsky, R J; Valerio, D.

In: Gene Therapy, Vol. 3, No. 2, 02.1996, p. 179-83.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Bone marrow gene transfer in three patients with adenosine deaminase deficiency

AU - Hoogerbrugge, P M

AU - van Beusechem, V W

AU - Fischer, A

AU - Debree, M

AU - le Deist, F

AU - Perignon, J L

AU - Morgan, G

AU - Gaspar, B

AU - Fairbanks, L D

AU - Skeoch, C H

AU - Moseley, A

AU - Harvey, M

AU - Levinsky, R J

AU - Valerio, D

PY - 1996/2

Y1 - 1996/2

N2 - Adenosine deaminase (ADA) deficiency results in severe combined immune deficiency disease (SCID), which is fatal without treatment. Allogeneic bone marrow transplantation (BMT) is the treatment of choice if an HLA-identical sibling bone marrow donor is available, resulting in almost 100% cure rate. BMT-related mortality is high in patients lacking such a donor. For these patients, efficient transfer of a recombinant ADA gene into hematopoietic stem cells is a therapeutic option if it results in the outgrowth of a 'genetically repaired' lymphoid system. Based on successful gene transfer studies in monkeys, we performed retrovirus-mediated gene transfer into CD34+ bone marrow cells of three patients with ADA deficiency. Two patients received bovine ADA conjugated to polyethylene glycol (PEG-ADA); in the third patient, PEG-ADA was started 4 months after gene transfer. Gene transfer resulted in a 5-12% transduction frequency of in vitro colony forming cells (CFU-Cs). No toxicity was observed during and after infusion of the graft. Following infusion of the transduced CD34+ cells, transduced granulocytes and mononuclear cells persisted in the circulation for 3 months. In addition, the gene was present in the marrow of one of the patients at 6 months after gene transfer. Expression of the gene was not detected. After this period, the gene could not be detected. In monkey studies we showed that myeloablation, which was not performed in the patients, may enhance engraftment of genetically modified cells. We hypothesize that lack of myeloablation, administration of bovine ADA and low numbers of transduced progenitor cells all may have contributed to the relative low numbers of transduced cells in the patients. Under these conditions, no selective advantage of the genetically corrected progenitor cells was observed.

AB - Adenosine deaminase (ADA) deficiency results in severe combined immune deficiency disease (SCID), which is fatal without treatment. Allogeneic bone marrow transplantation (BMT) is the treatment of choice if an HLA-identical sibling bone marrow donor is available, resulting in almost 100% cure rate. BMT-related mortality is high in patients lacking such a donor. For these patients, efficient transfer of a recombinant ADA gene into hematopoietic stem cells is a therapeutic option if it results in the outgrowth of a 'genetically repaired' lymphoid system. Based on successful gene transfer studies in monkeys, we performed retrovirus-mediated gene transfer into CD34+ bone marrow cells of three patients with ADA deficiency. Two patients received bovine ADA conjugated to polyethylene glycol (PEG-ADA); in the third patient, PEG-ADA was started 4 months after gene transfer. Gene transfer resulted in a 5-12% transduction frequency of in vitro colony forming cells (CFU-Cs). No toxicity was observed during and after infusion of the graft. Following infusion of the transduced CD34+ cells, transduced granulocytes and mononuclear cells persisted in the circulation for 3 months. In addition, the gene was present in the marrow of one of the patients at 6 months after gene transfer. Expression of the gene was not detected. After this period, the gene could not be detected. In monkey studies we showed that myeloablation, which was not performed in the patients, may enhance engraftment of genetically modified cells. We hypothesize that lack of myeloablation, administration of bovine ADA and low numbers of transduced progenitor cells all may have contributed to the relative low numbers of transduced cells in the patients. Under these conditions, no selective advantage of the genetically corrected progenitor cells was observed.

KW - Adenosine Deaminase/genetics

KW - Animals

KW - Antigens, CD34/analysis

KW - Cattle

KW - DNA/analysis

KW - Gene Expression

KW - Gene Transfer Techniques

KW - Genetic Vectors/genetics

KW - Hematopoietic Stem Cell Transplantation

KW - Hematopoietic Stem Cells

KW - Humans

KW - Infant

KW - Leukocytes/chemistry

KW - Macaca mulatta

KW - Proviruses

KW - Retroviridae/genetics

KW - Severe Combined Immunodeficiency/therapy

M3 - Article

VL - 3

SP - 179

EP - 183

JO - Gene Therapy

JF - Gene Therapy

SN - 0969-7128

IS - 2

ER -

Hoogerbrugge PM, van Beusechem VW, Fischer A, Debree M, le Deist F, Perignon JL et al. Bone marrow gene transfer in three patients with adenosine deaminase deficiency. Gene Therapy. 1996 Feb;3(2):179-83.