If you want to modify immune cells in the human body so that they can effectively fight a tumor or slow down an autoimmune disease, for example, you need reliable and safe tools. One of these is the "Sleeping Beauty" system developed at the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC). The MDCell Helmholtz Innovation Lab and the biopharmaceutical company PlasmidFactory are jointly preparing this system so that it will be suitable for gene therapy in the clinic in the future. The two partners have now extended their collaboration for a further two years.
"Sleeping Beauty 100x" is based on an element in the genetic material of fish that presumably copied itself 20 million years ago as a "jumping gene" (transposon) and was able to repeatedly insert itself into new positions in the fish DNA. Transposons mix up the genome and are therefore regarded as one of the motors of evolution. Dr. Zsuzsanna Izsvák and her colleagues have awakened the jumping gene from its evolutionary slumber, increased its activity 100-fold and made it usable for gene therapy. The "Sleeping Beauty" system can now introduce genes into the genome. It is safer, cheaper and more efficient than other methods, Izsvák emphasizes.
The modified gene sequence does not need a virus as a "cab" (vector) to its destination. The disadvantages associated with viruses in gene therapy are therefore eliminated. Instead, the system consists of two elements: the transposon pT4 - a ring-shaped DNA molecule (plasmid) in which the desired gene is inserted between two typical markers - and the genetic material for an enzyme called "SB100x", which cuts the desired gene out of the plasmid and guides it to its destination.
The MDCell Helmholtz Innovation Lab is now extending its collaboration with PlasmidFactory to optimize the "Sleeping Beauty" system.
Proven collaboration
MDCell and PlasmidFactory are further refining the system to make its use in human cells even safer. For example, the genetic material for the enzyme "SB100x" is already transcribed in the Petri dish and added to the cells to be modified as in vitro transcribed RNA (IVT RNA). The transposon "pT4" is also no longer a complete plasmid, as is often the case in bacteria. Instead, the PlasmidFactory has developed a technique in which a mini-ring (minicircle) is formed. Apart from the necessary markers, it consists almost entirely of the gene that is to be inserted.
"It is very important that the bacterial parts of the plasmids are omitted - to further improve the safety and efficacy of the SB100x transposon system," says Dr. Holger Hoff, head of MDCell. "And PlasmidFactory produces particularly high-quality minicircles, as they are very tightly twisted."
Both partners have extensive expertise. PlasmidFactory has know-how in the design and duplication of the "gene cabs", in patent issues and questions of approval. "We are currently establishing high-quality production processes for minicircle DNA in our special laboratory in Bielefeld, which are used for CAR-T cell therapy research," explains Dr. Martin Schleef, Managing Director of PlasmidFactory. MDCell, in turn, combines the research of various working groups with partners from industry, develops processes and provides rooms and equipment. Their common goal is to use Sleeping Beauty to genetically modify immune cells, for example, so that they can help patients again and make the system ready for clinical use. To achieve this, it must not only be safe, it must also be possible to mass produce it in consistent quality. "We are working together to establish the relevant protocols for GMP facilities," says Hoff.
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