Delivering the genes

Scripps Research Institute scientists find that cancer drug rapamycin may help bypass blood stem cell defenses

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LA JOLLA, Calif.—In a new study led by Associate Prof. Bruce Torbett of The Scripps Research Institute (TSRI), a team of researchers have cleared a major hurdle by solving the puzzle of how to bypass blood stem cells’ natural defenses and more efficiently insert disease-fighting genes into those cells’ genome.
The solution to the dilemma is rapamycin, a drug which is commonly used to slow cancer growth and prevent organ rejection. Torbett and his team discovered that the drug also enables delivery of a therapeutic dose of genes to blood stem cells while preserving stem cell function.
This discovery is considered a huge find toward making gene therapy a more achievable reality.
“We found that rapamycin stops stem cells from growing and allows more efficient vector gene entry,” Torbett tells DDNews.
“We are really excited to have leaped over this hurdle in gene therapy,” Torbett adds. “The bottom line is, ultimately, I’d like to see this use get to benefit patients.”
These findings, published in the online version of the journal Blood, could lead to more effective and affordable long-term treatments for blood cell disorders in which mutations in the DNA cause abnormal cell functions, such as in leukemia and sickle cell anemia.
Torbett and his team initially set out to test whether rapamycin, chosen for its ability to control virus entry and slow cell growth, could improve delivery of a gene to blood stem cells.
Viruses infect the body by inserting their own genetic material into human cells, he said. In gene therapy, however, scientists have developed  “gutted” viruses, such as the human immunodeficiency virus (HIV), to produce what are called “viral vectors” that carry therapeutic genes into cells without causing viral disease.
For a disease such as leukemia, in which mutations in the DNA cause abnormal cell function, efficiently targeting the stem cells that produce these blood cells could be a successful approach to halting the disease and prompting the body to produce healthy blood cells, he says.
“If you produce a genetic modification in your blood stem cells when you are five years old, these changes are lifelong,” Torbett notes. Furthermore, the “gene-modified stem cells can develop into many types of cells that travel throughout the body to provide therapeutic effects.”
However, because cells have adapted defense mechanisms to overcome disease-causing viruses, engineered viral vectors can be prevented from efficiently delivering genes, he points out.
So when scientists extract blood stem cells from the body for gene therapy, HIV viral vectors are usually able to deliver genes to only 30 to 40 percent of them, Torbett says. For leukemia, leukodystrophy or genetic diseases where treatment requires a reasonable number of healthy cells coming from stem cells, this number may be too low for therapeutic purposes.
This limitation prompted Torbett and his team, including TSRI graduate student Cathy Wang, the first author of the study, to test whether rapamycin could improve delivery of a gene to blood stem cells.
The researchers began by isolating stem cells from cord blood samples, Torbett said. They then exposed the blood stem cells to rapamycin and HIV vectors engineered to deliver a gene for a green florescent protein, providing a visual marker that helped the TSRI team track gene delivery.
“We saw a big difference in both mouse and human stem cells treated with rapamycin, where therapeutic genes were inserted into up to 80 percent of cells,” Torbett explains. “This property had never been connected to rapamycin before.”
The TSRI researchers also found that rapamycin can keep stem cells from differentiating as quickly when taken out of the body for gene therapy, allowing more time to work on extracted blood stem cells, he says, adding that once these cells leave the body, they begin to differentiate if manipulated into other types of blood cells, and lose the ability to remain as stem cells and pass on therapeutic genes.
“We wanted to make sure the conditions we will use preserve stem cells, so if we transplant them back into our animal models, they’ll act just like the original stem cells,” Torbett says. “We showed that in two sets of animal models, stem cells remained and produced gene-modified cells.”
Wang stated in a news release, “Our methods could reduce costs and the amount of preparation that goes into modifying blood stem cells using viral vector gene therapy. It would make gene therapy accessible to a lot more patients.”
The next steps are to carry out preclinical studies using rapamycin with stem cells in other animal models, then test whether the method is safe and effective in humans, Wang said. The team is also working to delineate the dual pathways of rapamycin’s method of action in blood stem cells.
In addition to Wang and Torbett, other authors of the study, “Rapamycin relieves lentiviral vector transduction resistance in human and mouse hematopoietic stem cells,” include Blythe D. Sather, Xuefeng Wang, Iram Khan, Swati Singh, Gabrielle Curinga and Carol H. Miao of the Seattle Children’s Research Institute; David J. Rawlings of the University of Washington School of Medicine and the Seattle Children’s Research Institute; Jennifer Adair, Amie Adams and Hans-Peter Kiem of the Fred Hutchinson Cancer Research Center; and Shanshan Lang of TSRI.
The abstract in the Blood journal states in part: “Transplantation of genetically modified hematopoietic stem cells (HSCs) is a promising therapeutic strategy for genetic diseases, HIV and cancer. However, a barrier for clinical HSC gene therapy is the limited efficiency of gene delivery via lentiviral vectors (LV) into HSCs … Collectively, rapamycin strongly augments LV transduction of HSCs in vitro and in vivo, and may prove useful for therapeutic gene delivery.”

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