Researchers have taken several steps to use stem cells to treat a rare genetic disease leaves people with skin so fragile that it blisters at the slightest touch. A trio of laboratory studies and animal reported today could help pave the way for a clinical trial to the disease called epidermolysis bullosa (EB).
While EB's quite rare, occurring in one in 20,000 births, about 500,000 people worldwide suffer from some form of the disease. It is caused by a defect in one of the many genes that encode proteins such as collagen, which connect the upper and lower layers of the skin. The genetic defect creates the fragile skin that is easily torn, which leads to painful blisters and sores. There is no cure; Doctors usually treat the symptoms by healing the wounds and treat infections. Those with severe forms of EB who survive childhood are also prone to skin cancer and often die of what their middle 40s.
therefew years, researchers have tried gene therapy in a single EB patient, using a virus to add a corrective gene in skin cells cultured from that person, then leaves grafting of them on his legs. Although the cells repaired seized, the risks of the virus used in the test and the challenges of growing enough cells to cover a large area have led researchers to look for other options.
Several groups have now turned to induced pluripotent stem (iPS) cells, a cell type created by reprogramming adult cells back to an embryonic state. These iPS cells can be induced to grow in large quantities from various adult tissues that are genetically adapted to a person and therefore less likely to be rejected by the immune system that cells from a donor.
continue A team of Columbia University's approach iPS cells recently took advantage of the fact that some patients with EB have skin cells that lose somehow pathogenic mutations and become healthy cells. Scientists have converted some of these revertant cells "" in iPS cells, then the cells increased skin called keratinocytes that express collagen type missing in patients. When grafted onto the back of a mouse strain with a weak immune system would not reject cells from a different species, keratinocytes increased in human skin and produces the correct form of collagen. Using revertant cells in this manner for EB could avoid the risks of gene therapy and "be a little more simple," said study leader Angela Christiano.
But only about 20% to 30% people with EB have revertant skin cells, so that other groups have adopted a more traditional approach. in a second study, Stanford University researchers in Palo Alto, California, has created iPS cells from skin cells taken from three different EB patients lack collagen type studied by the Columbia team. They then determined the genetic defect in stem cells before turning them back into keratinocytes. These steps can potentially introduce deleterious mutations, and the original cells of EB patients can also lead to cancer-causing mutations. But the team has reduced this risk by genetic screening and the bank that iPS cells free of harmful mutations. The cells grew as skin grafts on mice up to one month before the dead cells.
None of these studies showed that the cells could help treat the disease in an animal with EB. But in the third study, researchers in the lab of Josef Penninger at the Institute Molecular Biotechnology of the Austrian Academy of Sciences in Vienna did just that by differentiating iPS cells from mouse skin cells with the same defect as the EB patients studied by the Stanford group. They then repaired the collagen gene; transformed cells into fibroblasts, another type of skin cells; and injected under the skin of diseased mice. These cells form the skin layers which express the correct form of collagen for 18 weeks.
Together the three documents, published today in Science Translational Medicine "should provide much optimism that this approach has great legs," says Anthony Oro, who co -dirigé Stanford study with Marius Wernig. Both the group and the Columbia team requested funding to launch iPS cell treatment trials in EB patients.
Although reports are promising, they also show the challenges of using these cells for skin disease, said stem cell scientist Lorenz Studer of Memorial Sloan Kettering Cancer Center in New York City. He notes that researchers have not yet found the right recipe to produce human skin cells live longer than a few weeks. "this therapy is still a little waiting until the field can achieve long-term graft," said Studer.
Jakub Tolar of the University of Minnesota, Twin Cities, who is also studying iPS and gene therapy for EB, highlights another problem. The approach of the skin graft will not treat the internal problems that many patients suffer from EB due to the effects of the disease on the lining of the intestine and esophagus. Tolar is working on a solution riskier but more complete: give a bone marrow transplant EB patients genetically corrected cells made using iPS cells. Yet he is impressed by the current trio of papers. "It is gratifying to see that they have taken to this point," said Tolar.
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