Stem cell clonality and genotoxicity in hematopoietic cells

TY - JOUR

T1 - Stem cell clonality and genotoxicity in hematopoietic cells

T2 - gene activation side effects should be avoidable

AU - von Kalle, C

AU - Fehse, B

AU - Layh-Schmitt, G

AU - Schmidt, M

AU - Kelly, P

AU - Baum, C

PY - 2004/10

Y1 - 2004/10

N2 - Two serious adverse events involving activation of the LMO2 oncogene through retrovirus vector insertion in the otherwise extremely successful first gene therapy trial for X-linked severe combined immunodeficieny type 1 (SCID-X1) had initially caused widespread concern in the patient and research communities. Careful consideration 1 year after diagnosis of the second case still finds 12 of the treated patients clearly benefiting from gene therapy (freedom from treatment failure, 80%; survival 100%), a situation that should not portend the end of gene therapy for this disease, and is, in fact encouraging. While current approaches are justified to treat patients with otherwise life-threatening disorders, a broad consensus has developed that systematic basic research is required to further understand the pathophysiology of these serious adverse events and to provide new insights, enabling safer and more effective gene therapy strategies. With the continued success of SCID-X1 gene therapy in the majority of patients treated, it is of even greater importance to understand exactly which vector element or combination of elements predispose to toxicity. An in-depth study of the mechanisms behind the activation of the LMO2 and gammac genes will be highly instructive for the development of safer procedures and vectors. We summarize the central observations, ongoing experimental approaches, new concepts, and developments relevant to understanding, interpreting, and eventually overcoming the real and perceived obstacles posed by insertional mutagenesis due to gene transfer vectors.

AB - Two serious adverse events involving activation of the LMO2 oncogene through retrovirus vector insertion in the otherwise extremely successful first gene therapy trial for X-linked severe combined immunodeficieny type 1 (SCID-X1) had initially caused widespread concern in the patient and research communities. Careful consideration 1 year after diagnosis of the second case still finds 12 of the treated patients clearly benefiting from gene therapy (freedom from treatment failure, 80%; survival 100%), a situation that should not portend the end of gene therapy for this disease, and is, in fact encouraging. While current approaches are justified to treat patients with otherwise life-threatening disorders, a broad consensus has developed that systematic basic research is required to further understand the pathophysiology of these serious adverse events and to provide new insights, enabling safer and more effective gene therapy strategies. With the continued success of SCID-X1 gene therapy in the majority of patients treated, it is of even greater importance to understand exactly which vector element or combination of elements predispose to toxicity. An in-depth study of the mechanisms behind the activation of the LMO2 and gammac genes will be highly instructive for the development of safer procedures and vectors. We summarize the central observations, ongoing experimental approaches, new concepts, and developments relevant to understanding, interpreting, and eventually overcoming the real and perceived obstacles posed by insertional mutagenesis due to gene transfer vectors.

KW - Adaptor Proteins, Signal Transducing

KW - DNA Damage

KW - DNA-Binding Proteins/genetics

KW - Genetic Therapy/adverse effects

KW - Genetic Vectors/adverse effects

KW - Hematopoietic Stem Cells/cytology

KW - Humans

KW - LIM Domain Proteins

KW - Metalloproteins/genetics

KW - Proto-Oncogene Proteins

KW - Severe Combined Immunodeficiency/complications

U2 - 10.1053/j.seminhematol.2004.07.007

DO - 10.1053/j.seminhematol.2004.07.007

M3 - SCORING: Review article

C2 - 15508116

VL - 41

SP - 303

EP - 318

JO - SEMIN HEMATOL

JF - SEMIN HEMATOL

SN - 0037-1963

IS - 4

ER -