American Society of Gene Therapy (ASGT) Ad Hoc subcommittee on retroviral-mediated gene transfer to hematopoietic stem cells

Donald B. Kohn, Michel Sadelain, Cynthia Dunbar, David Bodine, Hans Peter Kiem, Fabio Candotti, John Tisdale, Isabelle Riviére, C. Anthony Blau, Robert E. Richard, Brian Sorrentino, Jan Nolta, Harry Malech, Malcolm Brenner, Kenneth Cornetta, Joy Cavagnaro, Katherine High, Joseph Glorioso

Research output: Contribution to journalArticle

133 Citations (Scopus)

Abstract

In summary, this review of findings in murine and large animal models and in human clinical trials indicates that the development of leukemia in the XSCID subjects was relatively unprecedented and not predicted by preclinical studies. No SAEs related to retroviral vectors were observed, except for a single report in a murine model and the two cases in the XSCID trial. However, in contrast to the very high number of gene-containing cells seen in the XSCID studies (and the Italian trial for ADA deficiency), most of the other clinical studies have been characterized by very low numbers of gene-containing cells in circulation (<1-2 years) and a lack of long-term persistence. Many subjects in the gene marking studies were patients with advanced malignant disease (undergoing therapeutic hematopoietic stem cell transplantation) to which they succumbed within months to a few years of participation in the gene transfer trial. Most treatments for genetic diseases were done without any cytoreductive therapy, and thus engraftment of gene-containing cells was in very low numbers. Thus, the lack of SAEs in these studies cannot be used to support the general safety of retroviral-mediated gene transfer to HSCs. One cannot make conclusions about the safety of gene therapy when there is not significant gene transfer to the relevant target cells. It is possible that the amount of gene transfer to HSCs in these studies was higher than detected by gene marking of PBCs, and the absence of lymphoproliferation indicates that this is not necessarily a problem. The few exceptional studies that did show more long-term persistence of gene-marked cells did not have any cases of leukemia or other complications.

Original languageEnglish
Pages (from-to)180-187
Number of pages8
JournalMolecular Therapy
Volume8
Issue number2
DOIs
StatePublished - Aug 1 2003
Externally publishedYes

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Hematopoietic Stem Cells
X-Linked Combined Immunodeficiency Diseases
Genes
Leukemia
Safety
Inborn Genetic Diseases
Hematopoietic Stem Cell Transplantation
Genetic Therapy
Therapeutics
Animal Models
Clinical Trials

ASJC Scopus subject areas

  • Molecular Biology

Cite this

American Society of Gene Therapy (ASGT) Ad Hoc subcommittee on retroviral-mediated gene transfer to hematopoietic stem cells. / Kohn, Donald B.; Sadelain, Michel; Dunbar, Cynthia; Bodine, David; Kiem, Hans Peter; Candotti, Fabio; Tisdale, John; Riviére, Isabelle; Blau, C. Anthony; Richard, Robert E.; Sorrentino, Brian; Nolta, Jan; Malech, Harry; Brenner, Malcolm; Cornetta, Kenneth; Cavagnaro, Joy; High, Katherine; Glorioso, Joseph.

In: Molecular Therapy, Vol. 8, No. 2, 01.08.2003, p. 180-187.

Research output: Contribution to journalArticle

Kohn, DB, Sadelain, M, Dunbar, C, Bodine, D, Kiem, HP, Candotti, F, Tisdale, J, Riviére, I, Blau, CA, Richard, RE, Sorrentino, B, Nolta, J, Malech, H, Brenner, M, Cornetta, K, Cavagnaro, J, High, K & Glorioso, J 2003, 'American Society of Gene Therapy (ASGT) Ad Hoc subcommittee on retroviral-mediated gene transfer to hematopoietic stem cells', Molecular Therapy, vol. 8, no. 2, pp. 180-187. https://doi.org/10.1016/S1525-0016(03)00212-0
Kohn, Donald B. ; Sadelain, Michel ; Dunbar, Cynthia ; Bodine, David ; Kiem, Hans Peter ; Candotti, Fabio ; Tisdale, John ; Riviére, Isabelle ; Blau, C. Anthony ; Richard, Robert E. ; Sorrentino, Brian ; Nolta, Jan ; Malech, Harry ; Brenner, Malcolm ; Cornetta, Kenneth ; Cavagnaro, Joy ; High, Katherine ; Glorioso, Joseph. / American Society of Gene Therapy (ASGT) Ad Hoc subcommittee on retroviral-mediated gene transfer to hematopoietic stem cells. In: Molecular Therapy. 2003 ; Vol. 8, No. 2. pp. 180-187.
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AU - Sadelain, Michel

AU - Dunbar, Cynthia

AU - Bodine, David

AU - Kiem, Hans Peter

AU - Candotti, Fabio

AU - Tisdale, John

AU - Riviére, Isabelle

AU - Blau, C. Anthony

AU - Richard, Robert E.

AU - Sorrentino, Brian

AU - Nolta, Jan

AU - Malech, Harry

AU - Brenner, Malcolm

AU - Cornetta, Kenneth

AU - Cavagnaro, Joy

AU - High, Katherine

AU - Glorioso, Joseph

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N2 - In summary, this review of findings in murine and large animal models and in human clinical trials indicates that the development of leukemia in the XSCID subjects was relatively unprecedented and not predicted by preclinical studies. No SAEs related to retroviral vectors were observed, except for a single report in a murine model and the two cases in the XSCID trial. However, in contrast to the very high number of gene-containing cells seen in the XSCID studies (and the Italian trial for ADA deficiency), most of the other clinical studies have been characterized by very low numbers of gene-containing cells in circulation (<1-2 years) and a lack of long-term persistence. Many subjects in the gene marking studies were patients with advanced malignant disease (undergoing therapeutic hematopoietic stem cell transplantation) to which they succumbed within months to a few years of participation in the gene transfer trial. Most treatments for genetic diseases were done without any cytoreductive therapy, and thus engraftment of gene-containing cells was in very low numbers. Thus, the lack of SAEs in these studies cannot be used to support the general safety of retroviral-mediated gene transfer to HSCs. One cannot make conclusions about the safety of gene therapy when there is not significant gene transfer to the relevant target cells. It is possible that the amount of gene transfer to HSCs in these studies was higher than detected by gene marking of PBCs, and the absence of lymphoproliferation indicates that this is not necessarily a problem. The few exceptional studies that did show more long-term persistence of gene-marked cells did not have any cases of leukemia or other complications.

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