New platform allows gene-edited stem cell therapies for DEB
Scientists say their work solves 'critical bottlenecks' in advancing therapy
Scientists have devised a new, more efficient method to create gene-edited stem cell therapies for dystrophic epidermolysis bullosa (DEB).
“Solving critical bottlenecks, we refine a practical and simplified … protocol for the generation of genetically corrected … skin grafts … for the long-term healing of DEB patient wounds,” the researchers wrote.
The team described their new methodology in a paper titled “A scalable and cGMP-compatible autologous organotypic cell therapy for Dystrophic Epidermolysis Bullosa,” published in Nature Communications.
Technological advancements spur new stem cell therapies
DEB, one of the four main types of epidermolysis bullosa, is caused by mutations in the gene COL7A1 , which provides instruction to make part of an important structural protein called type VII collagen. Without this protein, skin becomes abnormally fragile and prone to wounds and blisters, ultimately driving disease symptoms.
In the past several years, biological technologies have advanced by leaps and bounds. Among the most exciting new technologies are gene editing tools — ones that allow researchers to alter the genetic code of cells, potentially correcting disease-causing mutations — and induced pluripotent stem cells (iPSCs), where easily accessible cells like skin or blood cells essentially are reprogrammed into stem cells that can then be grown into new cell types, like healthy skin cells.
These technological advancements have opened new doors into potential treatment for genetic diseases like DEB. Some researchers now are asking if it might be possible to grow a DEB patient’s cells into iPSCs, then use gene editing to correct a disease-causing mutation and grow the stem cells into healthy skin cells. This ultimately might allow the production of skin grafts that use a patient’s own cells but don’t carry a disease-causing mutation.
Early preclinical work has shown that this is possible in theory — however, doing it at the scale that would be needed for use as a therapy in people is another matter entirely. Part of the problem is that growing patients’ cells into iPSCs and then performing gene editing requires two separate steps that are both time-consuming and labor-intensive.
In this study, scientists took advantage of recent technological breakthroughs in these fields to come up with a streamlined protocol in which a patient’s cells are grown into iPSCs and gene-edited to correct the disease-causing mutation, all in one step. The gene-edited iPSCs could then be quickly grown into the various layers of healthy human skin, forming grafts that could be used to treat patients.
According to the scientists, the entire process can be accomplished in about one-and-a-half months under optimal conditions.
Skin grafts using new technique successfully implanted in mice
The team of researchers, led by scientists at the Stanford University School of Medicine in California, demonstrated successful proof-of-concept for this technique using cells from four people with DEB.
Three of the patients carried the same disease-causing mutation in one of the two COL7A1 gene copies (two of them had it in the other copy as well), but the fourth carried different mutations — illustrating that, with the right setup, this process can be applied to patients with multiple types of mutations.
The scientists showed that, once this process was used to generate skin grafts, the grafts could be successfully implanted into the skin of mice, surviving to make new healthy skin tissue.
[This new platform] overcomes manufacturing and safety roadblocks and establishes a reproducible, safe, and [current Good Manufacturing Practice]-compatible therapeutic approach to heal lesions of DEB patients.
Importantly, the transplanted grafts did not show any evidence of cancerous growth, which is a concern with any gene-edited stem cells and particularly a concern in DEB, where the risk of skin cancer is already high. The gene-edited cells also showed minimal signs of any unexpected changes in the genetic code, which is another safety concern with gene editing.
An in-depth battery of tests already conducted by these scientists has shown that this technique can be feasibly implemented at scale using good manufacturing practices. That helps pave the way toward using this technology in trials of human participants.
The researchers concluded that their platform, which they dubbed the Dystrophic Epidermolysis Bullosa Cell Therapy or DEBCT, “overcomes manufacturing and safety roadblocks and establishes a reproducible, safe, and [current Good Manufacturing Practice]-compatible therapeutic approach to heal lesions of DEB patients.”
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