Gentherapie von Hämoglobinkrankheiten – aktuelle Konzepte und Herausforderungen

Zusammenfassung

Die β-Thalassämien und die Sichelzellerkrankung sind weltweit die häufigsten Einzelgendefekte, die konventionell nur durch eine lebenslang erforderliche Supportivtherapie oder kurativ mittels allogener Stammzelltransplantation behandelbar sind. Aktuell werden Gentherapiestrategien entwickelt, die nach Transduktion von hämatopoetischen Stammzellen durch lentivirale Vektoren zu einer Expression eines therapeutischen β-Globin-Gens oder zur therapeutischen Reexpression der fetalen Globinsynthese und damit des fetalen Hämoglobins (HbF) führen. Für die β-Thalassämie hat die Genadditionstherapie für eine ausgewählte Gruppe von Patientinnen und Patienten mit transfusionsbedürftiger Non-β⁰-Thalassaemia major nach konditionaler Zulassung durch die European Medicines Agency (EMA) im Juni 2019 einen ersten Grad klinischer Reife erreicht. In dieser Übersicht diskutieren wir darüber hinaus die Möglichkeiten und Herausforderungen von Genomeditierungsstrategien für die Hämoglobinkrankheiten, insbesondere durch Inaktivierung von BCL11A, des zentralen Inhibitors der postnatalen fetalen Hämoglobinsynthese. Insgesamt verspricht die Entwicklung der Gentherapie für die Hämoglobinkrankheiten eine relevante Chance für diese, auch in Deutschland zahlreicher werdenden Gruppe von Patientinnen und Patienten mit schweren, sowohl Lebensqualität als auch Lebenserwartung erheblich einschränkenden Erkrankungen.

Abstract

The β-thalassemias and sickle cell disease represent the most frequent single gene disorders worldwide. The standard of care for both conditions is either life-long supportive therapy or allogeneic stem cell transplantation. Currently, strategies for gene therapy are being developed, which are based on the lentiviral transduction of hematopoietic stem cells aiming at either re-establishing normal β-globin chain synthesis or at re-activating fetal γ-globin chain and HbF (fetal haemoglobin) expression. For a selected group of patients with transfusion dependent non-β⁰ thalassemia major the European Medicines Agency (EMA) conditionally licensed gene addition therapy in June 2019, which has thus reached the first step of clinical maturity. In this review, we also discuss the potential and the challenges of gene editing strategies for the hemoglobin diseases in particular by inactivating BCL11A, the central inhibitor of postnatal fetal hemoglobin synthesis. In sum, the development of gene therapy offers a relevant chance to this group of patients that has recently significantly increased in size also in Germany and who suffer from conditions that severely limit both, life expectancy and quality of life.

Schlüsselwörter

Gentherapie - Thalassämie - Sichelzellkrankheit

Key words

gene therapy - thalassemia - sickle cell disease

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