SAN FRANCISCO—It’s been traditionally, and rudely, said that “children should be seen and not heard.” But what of a relative youngster in the world of life sciences, CRISPR gene-editing technology? Well, it looks like some of the progeny produced from this relative newcomer will work a great deal better if they are not seen, and thus can do their work better.
Specifically, researchers at the University of California, San Francisco (USCF) have used CRISPR/Cas9 gene-editing technology to create the first pluripotent stem cells that are, as noted by UCSF public information rep Jason Alvarez in a piece for the USCF website, functionally “invisible” to the immune system, a feat of biological engineering that, in laboratory studies, prevented rejection of stem cell transplants.
“Scientists often tout the therapeutic potential of pluripotent stem cells, which can mature into any adult tissue, but the immune system has been a major impediment to safe and effective stem cell therapies,” noted Dr. Tobias Deuse, the Julien I.E. Hoffman, MD, Endowed Chair in Cardiac Surgery at UCSF and lead author of the new study, published Feb. 18 in the journal Nature Biotechnology.
Just as with transplanted organs, transplanted stem cells or other cells have the potential to set off the body’s alarms and send out an immune response that leads to rejection.
“We can administer drugs that suppress immune activity and make rejection less likely. Unfortunately, these immunosuppressants leave patients more susceptible to infection and cancer,” explained Dr. Sonja Schrepfer, the study’s senior author and director of the UCSF Transplant and Stem Cell Immunobiology (TSI) Lab at the time of the study.
Notes Alvarez in his UCSF article: In the realm of stem cell transplants, scientists once thought the rejection problem was solved by induced pluripotent stem cells (iPSCs), which are created from fully-mature cells, like skin or fat cells, that are reprogrammed in ways that allow them to develop into any of the myriad cells that comprise the body’s tissues and organs. If cells derived from iPSCs were transplanted into the same patient who donated the original cells, the thinking went, the body would see the transplanted cells as “self,” and would not mount an immune attack.
Practically speaking, though, clinical use of iPSCs has proven more difficult than the theories might have suggested, given that many patients’ cells prove unreceptive to reprogramming for as-yet-unknown or little-understood reasons—not to mention the expense and time to produce iPSCs for every patient who would benefit from stem cell therapy.
“There are many issues with iPSC technology, but the biggest hurdles are quality control and reproducibility. We don’t know what makes some cells amenable to reprogramming, but most scientists agree it can’t yet be reliably done,” Deuse said. “Most approaches to individualized iPSC therapies have been abandoned because of this.”
As such, Deuse and Schrepfer wanted to explore the concept of creating “universal” iPSCs. They describe in their paper that after altering the activity of just three genes, their iPSCs were able to avoid rejection after being transplanted into histocompatibility-mismatched recipients with fully functional immune systems.
“This is the first time anyone has engineered cells that can be universally transplanted and can survive in immunocompetent recipients without eliciting an immune response,” Deuse noted.
When the researchers transplanted their “triple-engineered” mouse stem cells into mismatched mice with normal immune systems, they observed no rejection. They then transplanted similarly engineered human stem cells into humanized mice with the same result.
Going beyond just stems cells into more organ-related territory, the researchers derived various types of human heart cells from these triple-engineered stem cells, which they again transplanted into humanized mice. The stem cell-derived cardiac cells were able to achieve long-term survival and even began forming rudimentary blood vessels and heart muscle, raising the possibility that triple-engineered stem cells may one day be used to repair failing hearts.
“Our technique solves the problem of rejection of stem cells and stem cell-derived tissues, and represents a major advance for the stem cell therapy field,” Deuse said. “Our technique can benefit a wider range of people with production costs that are far lower than any individualized approach. We only need to manufacture our cells one time and we’re left with a product that can be applied universally.”
In other March stem cell news from UCSF, researchers placed a gene into the brains of patients with moderately advanced Parkinson’s disease (whose symptoms were no longer controlled by their medications), reportedly resulting in a reduction of the severity of motor symptoms in those patients. In the Phase 1 trial led by UCSF, 15 patients were able to acquire up to three hours daily of extra “on-time,” which refers to the period in which their medication was effective without causing the involuntary muscle movements known as dyskinesia, a frequent side effect of longer-term medication use. Additionally, patients were able to decrease their Parkinson’s medication by up to 42 percent, depending on the amount of the brain that was infused and the dose of therapy.
For the study, which was published in print on March 26 in the Annals of Neurology, neurosurgeons used a technique developed by Dr. Krystof Bankiewicz of the UCSF Department of Neurosurgery, involving minimal exposure of the brain. Bankiewicz creates novel approaches for the delivery of therapeutic agents, including gene therapy, to specific areas of the brain for conditions ranging from brain tumors to Alzheimer’s disease.
“This is the first gene therapy trial for Parkinson’s disease trial in which intra-operative MRI-guided monitoring was used,” noted first author Dr. Chad Christine of the UCSF Department of Neurology and the Weill Institute for Neurosciences. “This allowed us to visualize and guide the infusion of the treatment into the brain in real time, to ensure delivery to the area that should provide maximum benefit.”
