Aktuelle gentherapeutische Behandlungsansätze bei Hämoglobinopathien

ZUSAMMENFASSUNG

Die Erfolge des Gentransfers in hämatopoetische Stammzellen bei Säuglingen mit schweren Immundefekten haben das Interesse geweckt, dieses Behandlungskonzept auch bei Patienten mit Hämoglobinopathien anzuwenden. In klinischen Studien wurde gezeigt, dass durch lentiviralen Transfer eines modifizierten β-Globingens in autologe hämatopoetische Stammzellen bei der Mehrzahl der β-Thalassämie-Patienten eine Transfusionsunabhängigkeit erreichbar ist und Sichelzellpatienten keine vasookklusiven Krisen mehr erleiden. Das Auftreten von zwei Leukämiefällen bei Sichelzellpatienten nach dieser Form der lentiviralen Gentherapie hat verdeutlicht, dass Weiterentwicklungen sinnvoll sind, um das Risiko von Integrationsereignissen und hämatopoetischen Neoplasien zu minimieren. Mit der neuartigen, im Jahr 2020 mit dem Nobelpreis ausgezeichneten Technologie der zielgerichteten CRISPR/Cas9-basierten Geneditierung hat ein solches Therapieverfahren kürzlich Einzug in die Klinik gehalten. In proof-of-concept-Studien konnte gezeigt werden, dass die CRISPR/Cas9-vermittelte Ausschaltung des erythrozytären Transkriptionsfaktors BCL11A in autologen hämatopoetischen Stammzellen die Expression fetalen Hämoglobins (HbF) reaktiviert und dass durch die stabile Produktion von HbF bedeutsame therapeutische Effekte bei Patienten mit Thalassämie und Sichelzellerkrankung erzielt werden.

ABSTRACT

The success of hematopoietic stem cell gene therapy in children with severe combined immunodeficiency has stimulated profound interest in implementing similar therapeutic strategies for patients with hemoglobinopathies. Clinical studies have shown that after lentiviral gene transfer of a modified β-globin gene into autologous hematopoietic stem cells the majority of β-thalassemia patients reach transfusion independency and patients with sickle cell disease do not experience further vasoocclusive events. The recent occurence of two leukemia cases in sickle cell patients after this form of treatment has shown that further development of gene therapy is needed to minimize the risk of unintentional genomic integration and subsequent hematologic malignancy. The nobel prize-winning approach of targeted CRISPR/Cas9-based genome editing has recently entered the clinic. Proof-of-concept studies have revealed that CRISPR/Cas9-mediated disruption of the erythroid-specific transcription factor BCL11A in autologous hematopoietic stem cells reactivates fetal hemoglobin (HbF) expression and that the resulting stable production of HbF provides meaningful therapeutic effects in patients with thalassemia and sickle cell disease.

Schlüsselwörter

Sichelzellerkrankung - β-Thalassämie - retroviraler Gentransfer - CRISPR/Cas9-Geneditierung - HbF-Induktion

Keywords

Sickle cell disease - β-Thalassemia - retroviral gene transfer - CRISR/Cas9 gene editing - HbF induction

Publication History

Received: 16 July 2021

Accepted: 26 July 2021

Article published online:
25 February 2022

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