‘Hit-and-run’ technology could improve immunotherapy and HIV cure research.

Scientists seeking a simple and gentle way to provide short-term gene therapy have a new tool: nanoparticles. In a paper published August 30 in the journal Nature Communications, Dr. Matthias Stephan at Fred Hutchinson Cancer Research Center describes nanoparticles he has developed that can streamline the delivery of bundled genetic material to specific cells.

“What we’re doing is ‘hit-and-run’ gene therapy,” a strategy in which a brief change to certain cells can have a permanent therapeutic effect, said Stephan, an immunobioengineer who led the study.

Currently, scientists pursuing gene therapy must choose either targeted approaches that permanently alter cells’ DNA, or short-term approaches that are damaging to cells and can’t be restricted to a particular cell type. Now there is a third option.

“It’s a really cool technology,” co-author and Hutch colleague Dr. Hans-Peter Kiem said of the new nanoparticles. Kiem, who holds Fred Hutch’s Endowed Chair for Cell and Gene Therapy, is a bone marrow transplant specialist who is using gene therapy to improve treatment for glioblastoma, HIV and genetic diseases like Fanconi anemia and hemoglobinopathies.

The nanoparticles’ ability to gently and temporarily provide gene-editing proteins to specific cells is “really the key” that makes the new approach stand out, he said. The approach may also be simple enough to — someday — make short-term gene therapy feasible around the world, even in areas with little or none of the specialized technology now needed to genetically engineer cells.Our cells run on proteins, and our DNA carries the “recipes” for all our proteins in the form of genes. When a genetic engineer adds a new gene to a cell, the cell “reads” the gene and produces a new protein — and gets whatever capabilities that protein provides.

Scientists are already using this careful rejiggering of cells’ DNA to improve health. For example, pioneers in cellular immunotherapy aim to save the lives of cancer patients by giving them immune cells genetically rewired to destroy the cancer.

Until now, genetic engineers had to choose between two methods:

The first are long-term strategies, such as those used in cellular immunotherapy or stem-cell gene therapy. These rely on carefully constructed carrier molecules that only enter certain cells and, once inside, stitch new genes into those cells’ DNA. But that stitching endures through a cell’s lifetime — which poses a problem if the genes that scientists want to introduce could have negative long-term effects.

The second method, called electroporation, does not permanently alter cells’ DNA, but it still has significant drawbacks, said Kiem. Electroporation “is very rough on cells. And we can’t really target any particular cells,” he said.

In electroporation, electric currents open holes in cells’ outer membranes. Using this method, researchers like Kiem can slip in messenger RNA, a type of genetic material that works like messages written in disappearing ink: It carries protein-building instructions from genes to protein-building factories elsewhere in the cell and then quickly degrades. If researchers slip messenger RNA for a specific protein into cells using electroporation, those cells can only build that protein during the short period before the messenger RNA disintegrates.

During electroporation, however, the membrane of every cell exposed to the current becomes porous. If scientists need to be selective about which cells they modify, they must go through more complex steps to separate out those cells.

Now, Stephan has brought together the best of both methods in a gentle, targeted and transient technique.