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Simple Cell Programming Designed for Gene Therapies

Matthias Stephan

Matthias Stephan (Stephan Lab)

31 August 2017. A simpler technique using nanoscale particles was shown in lab tests to deliver messenger RNA to reprogram cells for gene therapies, including changes in T-cells in the immune system now approved to treat a type of leukemia. A team from Fred Hutchinson Cancer Research Center and University of Washington in Seattle describe the process in yesterday’s issue of the journal Nature Communications.

Researchers led by Fred Hutch Center immunologist and University of Washington bioengineering professor Matthias Stephan are seeking to simplify ways of producing gene therapies for cancer and other diseases, which now require multiple steps and complex customized procedures that drive up costs and increase risks for patients. The methods designed by Stephan and colleagues, called hit-and-run programming, use materials in nanoparticles to deliver messenger ribonucleic acid or RNA, a single strand of nucleic acid related to DNA with the instructions used by cells to produce the amino acids in proteins for carrying out functions in the body.

The “hit-and-run” in the name also refers to the temporary nature of the changes made in cells for gene therapies. By limiting the time that changes in cells occur, gene therapies can be made safer for patients by reducing the time that these changes put the patient at risk. The team’s techniques can also replace use of high-voltage electric shocks, called electroporation, that perforates cells to enable the transfer of DNA or RNA in gene therapies.

The researchers’ techniques carry synthetic messenger RNA in nanoparticles made of a biodegradable polymer coated with ligands, or binding molecules, specific to the targeted cell types. After binding to the target cells, the nanoparticles cross the cell membranes and deliver the messenger RNA into cells that then express the desired therapeutic proteins.

The team tested the technique in the lab with three types of gene therapies, two of which involve chimeric antigen receptor, or CAR, proteins that enhance T-cells in the immune system, being tested as treatments for leukemia and other diseases at the Fred Hutch Center. FDA yesterday approved the first CAR T-cell therapy for a form of leukemia, made by the pharmaceutical company Novartis. As reported in Science & Enterprise in April 2017, Stephan’s lab is working on methods to simplify CAR T-cell treatments with cell reprogramming to make them safer for patients.

One of the techniques tested in the new study delivers a gene-editing agent, known as a megaTal nuclease, encoded with messenger RNA into a CAR T-cell. The editing agent removes genes that could cause T-cells to attack healthy tissue, but leaves the genes expressing cancer-fighting proteins. A second test transfers “memory” functions into T-cells, giving them the ability to regenerate cancer-fighting proteins should the same type of cancer cells reappear.

A third type of cell reprogramming applies the technique to hematopoietic, or blood-forming stem cells. In these tests, researchers inserted a gene in hematopoietic stem cells that produce blood cells better able to withstand chemotherapy drugs for treating glioblastoma, an aggressive form of brain cancer. The temporary reprogramming also protects sensitive brain cells from damage if continued beyond the quick treatment. Co-author and Fred Hutch Center colleague Hans-Peter Kiem studies gene therapies for treating glioblastoma, HIV, and inherited diseases.

The simplicity of the technology extends to the transport and handling of the nanoparticles. The researchers say the nanoparticles can be dried for easy shipping and handling, needing only water to reconstitute their potency. The team envisions preparing gene therapies for patients anywhere in the world, including regions with limited resources.

Simplified nanotech cell reprogramming still needs further tests in the lab, including on animals, before they’re ready for human clinical trials. Nonetheless, Stephan filed for U.S. and international patents on the technology.

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