Retroviral gene therapy in Germany with a view on previous experience and future perspectives

Abstract

Gene therapy can be used to restore cell function in monogenic disorders or to endow cells with new capabilities, such as improved killing of cancer cells, expression of suicide genes for controlled elimination of cell populations, or protection against chemotherapy or viral infection. While gene therapies were originally most often used to treat monogenic diseases and to improve hematopoietic stem cell transplantation outcome, the advent of genetically modified immune cell therapies, such as chimeric antigen receptor modified T cells, has contributed to the increased numbers of patients treated with gene and cell therapies. The advancement of gene therapy with integrating retroviral vectors continues to depend upon world-wide efforts. As the topic of this special issue is "Spotlight on Germany," the goal of this review is to provide an overview of contributions to this field made by German clinical and research institutions. Research groups in Germany made, and continue to make, important contributions to the development of gene therapy, including design of vectors and transduction protocols for improved cell modification, methods to assess gene therapy vector efficacy and safety (e.g., clonal imbalance, insertion sites), as well as in the design and conduction of clinical gene therapy trials.

Fig. 1. Several mechanisms can be employed to enrich gammaretroviral and lentiviral vector-modified cells in vitro or in vivo.

For example, antibodies can be used to purify modified cells transduced with vectors designed to express truncated forms of CD34 (tCD34) or the low-affinity nerve growth receptor (ΔLNGFR). Cells can be engineered to express suicide genes such as the Herpes simplex virus thymidine kinase (scHSVtk) or variants (e.g., TK007) to allow elimination of cells in the case of adverse events. Cells can also be modified to express the multidrug resistance protein MDR-1 or the methylguanine methyltransferase P140K mutant (MGMT^P140K) to endow improved resistance against medications such as chemotherapy so that only the modified cells (cells with the red rectangle) persist upon drug treatment. Knockout of receptors like CCR5 and CXCR4 can protect cells from HIV-1 infection. Furthermore, modification of cells to express small membrane-bound C peptides such as T20 and C46 can also prevent HIV-1 infection of modified cells. Retroviral particles were created with Biorender.com.