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Gentherapie der SCID-X1

Gene therapy of SCID-X1

  • Leitthema: Seltene Krankheiten, Teil 1
  • Published:
Bundesgesundheitsblatt - Gesundheitsforschung - Gesundheitsschutz Aims and scope

Zusammenfassung

SCID-X1 ist eine X-chromosomal vererbte Form der schweren kombinierten Immundefizienz, die durch inaktivierende Mutationen im IL2RG-Gen verursacht wird. Dieses Gen kodiert für die gemeinsame γ-Kette der Interleukinrezeptoren (Interleukin 2 receptor common gamma chain, Interleukin-2-Rezeptor-γ-Kette, IL2RG). Die betroffenen Jungen können 2 Haupttypen der Effektorzellen des Immunsystems nicht entwickeln (T-Zellen und NK-Zellen) und leiden zudem unter einer Funktionsstörung der B-Zellen. Eine alleinige Therapie mit antibiotischen Medikamenten und Immunglobulinen ist unzureichend. Sofern keine kausale Behandlung angeboten wird, sterben die Kinder oftmals im ersten Lebensjahr. Für ein Drittel der Patienten besteht die Möglichkeit der Transplantation von Knochenmark eines vollständig immunkompatiblen Spenders, die im Regelfall zur Heilung ohne wesentliche Nebenwirkungen führt. Andere Formen der Knochenmarktransplantation sind jedoch mit schweren und potenziell letalen Nebenwirkungen verknüpft. Im vergangenen Jahrzehnt haben Wissenschaftler daran gearbeitet, neue Behandlungsmöglichkeiten mittels Gentransfer einer intakten Kopie des IL2RG-Gens in patienteneigene, d. h. autologe, hämatopoetische Zellen zu entwickeln. Dieses Gentransferverfahren war hochgradig effektiv, sofern es bei jungen Patienten angewendet wurde. Jedoch entwickelten einige Patienten später eine Leukämie, die auf eine Aktivierung zellulärer Protoonkogene infolge der ungezielten Integration des Gentransfervektors in das Genom der hämatopoetischen Zellen zurückgeführt werden konnte. Eine verbesserte Vektortechnologie in Kombination mit anderen Protokollmodifikationen wird dieses Risiko in künftigen Gentherapiestudien wahrscheinlich senken können.

Abstract

X-linked severe combined immunodeficiency (SCID-X1) is an inherited disease caused by inactivating mutations in the gene encoding the interleukin 2 receptor common gamma chain (IL2RG), which is located on the X-chromosome. Affected boys fail to develop two major effector cell types of the immune system (T cells and NK cells) and suffer from a functional B cell defect. Although drugs such as antibiotics can offer partial protection, the boys normally die in the first year of life in the absence of a curative therapy. For a third of the children, bone marrow transplantation from a fully matched donor is available and can cure the disease without major side effects. Mismatched bone marrow transplantation, however, is complicated by severe and potentially lethal side effects. Over the past decade, scientists worldwide have developed new treatments by introducing a correct copy of the IL2RG-cDNA. Gene therapy was highly effective when applied in young children. However, in a few patients the IL2RG-gene vector has unfortunately caused leukaemia. Activation of cellular proto-on-cogenes by accidental integration of the gene vector has been identified as the underlying mechanism. In future clinical trials, improved vector technology in combination with other protocol modifications may reduce the risk of this side effect.

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Authors and Affiliations

  1. Medizinische Hochschule Hannover, BRD

    Christopher Baum, A. Schambach & U. Modlich

  2. Cincinnati Children's Hospital Medical Center, Cincinnati, USA

    Christopher Baum

  3. Institute of Child Health, London, GB

    A. Thrasher

  4. Experimentelle Hämatologie, Medizinische Hochschule Hannover, Carl-Neuberg-Straße 1, 30625, Hannover, BRD

    Christopher Baum

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  1. Christopher Baum
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  2. A. Schambach
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  4. A. Thrasher
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Correspondence to Christopher Baum.

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Baum, C., Schambach, A., Modlich, U. et al. Gentherapie der SCID-X1. Bundesgesundheitsbl. 50, 1507–1517 (2007). https://doi.org/10.1007/s00103-007-0385-5

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