A research team from the Paul-Ehrlich-Institut has succeeded in transferring individual therapeutic genes into mouse cytotoxic T cells using cell type-specific viral gene shuttles. This may open up new approaches for treating genetic diseases and cancer.
Gene therapy involves vectors that insert genetic information into a patient's somatic cells to compensate for previously impaired cell functions or to equip the somatic cells with new functions.
Cytotoxic T lymphocytes (CTLs) are white blood cells. These “killer cells” selectively destroy certain somatic cells, such as cells that are infected with a pathogen or that have been transformed into cancer cells. But CTLs don't recognise all cancer cells. Therefore, research is being carried out on how to genetically modify the T cells of a person suffering from cancer in such a way that the CTLs can recognise and kill the cancer cells in the body.
Viral vectors (lentiviral particles and AAV particles) are often used for gene transfer. These are altered, non-replicable virus particles, which are also referred to as gene shuttles or viral vectors. Vectors can transfer a therapeutic gene to somatic cells, which then become genetically modified.
Appropriately designed animal models are required for the development of new gene therapeutics. The introduction of genes into white blood cells (lymphocytes) of mice was a major technical challenge for a long time due to low efficiency and a lack of cell type specificity. Some CTLs carry the cell surface marker CD8. Professor Christian Buchholz's research team took advantage of this. The researchers produced designed ankyrin repeat proteins (DARPins), which bind to the CD8 molecule of mouse cells and decorated the surface of viral vectors with these CD8-binding DARPins. The resulting novel gene shuttles were thus able to genetically modify CD8-positive mouse CTLs with a very high efficiency and a selectivity of over 99 percent. The method is also so promising because the cell type specificity of the vectors can be changed by replacing one DARPin with another.
We were surprised by the efficiency of the new cell type-specific gene shuttles. They could represent an important milestone for the development of future gene therapies in the immunotherapy field.
Prof Dr Christian Buchholz (Head of the Molecular Biotechnology and Gene Therapy Research Group)
Michels A, Frank AM, Günther DM, Mataei M, Börner K, Grimm D, Hartmann J, Buchholz CJ (2021): Lentiviral and adeno-associated vectors efficiently transduce mouse T lymphocytes when targeted to murine CD8.
Mol Ther Methods Clin Dev 23: 334-347.