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- Therapy gene gets a high-stakes test
at the time of his birth, 41 years ago in Germany, Oliver Semler had already broken a bone, a thin pencil rib. This, arched his femurs, and a second fracture at the age of two days doctors said he had osteogenesis imperfecta (OI), a debilitating genetic disease that makes bones fragile and often break easily being pushed to school, for example, or slipping on wet leaves outside. Or, as in the case of Semler, acrobatics in the uterus. "I had a cast two or three times a year," said Semler, who lost many of its fractures, but has undergone 27 surgeries to repair the worst of them. "To my colleagues at school, it was normal. Oliver is not there 2 or 3 days, and he returned to school with a cast."
We have to do a clinical trial before people are willy-nilly.
improbably, given the severity of his illness, Semler avoided life in a wheelchair, but its growth was slowed and he stands 4 feet 8 inches tall. He attended medical school and became a pediatrician at the University of Cologne in Germany, where he takes care of 250 children with his condition. Semler is now preparing for the first time in OI and beyond :. A clinical trial of a stem cell treatment for the afflicted fetus, which aims to give them a better start in life than himself had
The trial, still being planned, is one of a handle being designed in Europe and the US to perhaps the most difficult patient population, it is: pregnant women and their fetuses. After decades of dashed hopes raised and, paediatricians, immunologists, and others are cautiously hoping that new biological knowledge and a push for treating parent-to-be could reverse the trend of stem cell therapy prenatal. "I think [there’s] much of an understanding of what is possible, what is safe, what is ethical," says Anna David, who studies fetal therapy at University College London and collaborates with Semler on the trial of OI.
Even the tests with only 30 or so mothers, the target for the study of OI require Herculean effort: a dozen academic partners and industry, dozens of doctors, million . A high-profile failure or worse, an injury to the mother or fetus, could define the decades field. "That's what keeps me awake at night," said David. "Security, trying to tick all the boxes, thinking as much as possible" on everything that could go wrong. Some fetuses have been treated on an ad hoc basis, with encouraging results, and it is a stimulating factor trials. But then is the probability that a bottle of good cells, administered at the right time, could stop a devastating disease before birth.
In the 1980s, when Semler was in elementary school, hopes ran high for the fetus treatment with stem cells. Because the immune system of the fetus is still in development and some of his guards, such as T cells, are not fully functional, doctors believed that the fetus would easily accept cells unlike abroad, even a baby, who may need chemotherapy or other toxic treatments to suppress the immune system. The transplanted cells would grow into healthy blood cells, immune cells, or other fetal parts were missing, thought has therefore stop the damage that a disease has already been inflicted in the womb. Maria Grazia Roncarolo, then a young pediatric immunologist, recalls the heady days in Lyon, France, where this theory was put to the test.
In 1988 and 1989 the Hôpital Edouard Herriot, two fetuses whose blood cell markers showed they had serious immune disorders became the first to receive a transplant of cells. Doctors led by Jean-Louis Touraine infused through the umbilical vein with blood stem cells from 7 to 10 weeks of age aborted fetuses. Roncarolo helped supervise the first baby after birth. With a little boy squirming in front of her, "I'm really totally excited," she said. "I thought I found a way to cure all genetic diseases. My young complete naivety, I thought I had found a solution."
A third fetus everyone on Earth. Instead of an immune deficiency, he had thalassemia, a disease potentially fatal blood. Hoping to treat the fetus when his immune system was particularly primitive and disease at a nascent stage, the doctors infused stem cells into the abdominal cavity of the fetus at 12 gestational weeks. In their defense, the cells were rejected and the transplant failed.
"The assumption that we had that the fetus was tolerant [of foreign cells] was wrong," said Roncarolo. Brutally disappointed, she revamped her career, returned to basic research and now works at the University Stanford in Palo Alto, California, where she is studying stem cell transplant and immune tolerance. Meanwhile, the rest of the Lyon team persevered, but the results were disappointing. Two fetuses died before birth of the treatment. in two other cells-all of aborted fetuses-graft didnt at that time, doctors stopped their efforts
Externally, the interest in stem cell therapy for fetal faded. . But behind the scenes, a small cohort of researchers undertook a trip many years to understand why it did not work when immunology suggested he should. pregnancy is a unique, two genetically distinct beings that intertwine without rejecting the other-a framework that, at least in theory, should provide an opening for cell therapy.
In the late 00s came a string of discoveries that helped explain the successes and failures. For one, researchers learned that fetal T cells are actually able to reject the invaders if a microbe or transplantation of cells more easily than foreign thought. Later, other researchers have found that it is probably not only the fetus which had condemned these grafts anterior cells. maternal immune cells are inevitably flow through the fetus, and in the mouse studies, these cells have rebelled against the donor cells.
A group led by Mike McCune at the University of California, San Francisco (UCSF), however, found an encouraging phenomenon: Some of fetal T cells are primed T cells to convert regulators supposedly which can tolerate foreigners, especially the cells of the mother. In mice, "if you match the graft mom, [nearly] all fetuses that you can transplant graft," said Tippi MacKenzie, pediatric surgeon at UCSF. She began to wonder if cells mother donor could be the most likely to be accepted. "it was the eureka moment," she said.
Mackenzie and others have also found that in animals, higher doses of donor maternal cells were more effective, and inject them into the blood of over increased success fetus. In humans, this becomes possible after gestation of 18 weeks, channeling the cells through the umbilical vein.
drastic solutions As science plugged along, desperate parents sought. In early 02, Madeleine and Stefan Karlsson, living in Uppsala, Sweden, and pregnant with their first child were a rollercoaster of uncertainty. An ultrasound at 20 weeks had raised red flags, but additional tests implemented anything. At 25 weeks, doctors "have discovered that something is wrong," recalls Stefan Karlsson. "After that, we have ultrasounds every week, and next week everything was fine, and the week after that something wrong again, but nobody knew what. "at 30 weeks gestation, a little more than 2 months before normal delivery- doctors shipped out fetal cells for analysis. The results were devastating. The Karlssons learned that their daughter had OI, later diagnosed as the most severe form of type III. only one other child in the world, Canada has been identified by the same mutation. the baby died at the age of 5 months.
fractures As a child, Oliver Semler was repeated.
Courtesy J. Oliver Semler
the Karlssons were referred to the Karolinska university hospital in Stockholm, where doctors suggested a radical strategy: the harvest of a specific type of stem cells from the liver of an aborted fetus and infuse through the vein umbilical in the fetus that Madeleine was wearing. The family agreed.
"We have transplanted about 6 million cells," says Cecilia Götherström Karolinska, which produced the cells. The stem cells used, mesenchymal stem cells (MSCs), are supposed to cause less vigorous immune response that the blood stem cells, mesenchymal stem cells can grow into bone, and other connective tissues. the hope was that MSCs would take hold and
produce new healthy bone.
the transplanted cells are a genetic match to the mother or fetus, the Karlssons appoint Olivia Nevertheless, at least some of them grafted. When Olivia was 9 months the cells of the donor biopsy revealed a mixed bone with its own
at first, Olivia did better than expected .. But doctors around his sixth birthday, she began to deteriorate and suffered a series of fractures. Finally, Götherström Olivia and her colleagues transplanted back more MSCs from the same donor tissue. Fractures Olivia diminished, and it was transplanted back every 4 years since. Now aged 14, she has not had a fracture in 18 months, surprising his doctors. The father of Olivia, she said swimming for physical therapy, enjoys sewing, arts and crafts, and like most teenagers, clothing stores and spending time with his friends.
Götherström knows that without a control group, there is no way to be sure that MSCs helped Olivia. However, encouraged by the Olivia experience, she and her colleagues later fetal MSCs shipped to Singapore for further treatment of a fetus with OI and infused a third of parents traveled to Sweden their home in Ireland; this child is now a toddler. And, with others, Götherström began to lay the foundation to see if in utero therapy was really made a difference. "We have to do a clinical trial before people are willy-nilly," said David UK, particularly because interest in such treatments may increase as it becomes easier to diagnose serious problems in utero.
There are two years, and Semler Götherström met at a conference on OI in Wilmington, Delaware. stem cells Until then transplanted Semler had not considered a viable treatment for the disorder. But he knew better than almost everyone that severe OI stand before birth, when the skeleton is still in training. On ultrasound, doctors detect shortened leg bones and even fractures. MSCs supply as soon as possible, Semler thought, could give a fetus a better chance to build healthy bone without the side effects of a bone marrow transplant after birth. And Götherström thought infusing the cells before birth had a better chance of working in part due to differences in the fetal circulation: The cells infused into the bloodstream are less likely to get stuck in the lungs and never surrender to their destination than they are in a baby.
V. Altounian / Science
A test of OI, called BOOSTB4, now sharpens towards the starting line. Götherström, David, Semler, and others have obtained more than $ 9 million from the European Union and the Swedish Research Council, and are developing their protocol. Starting later this year, they hope to begin recruiting 15 families across Europe with fetuses made by ultrasound and DNA tests have severe OI and in the second or third quarter infuse with MSCS from liver cells fetal, like those received Olivia. Infants receive additional infusions after birth. They will be compared to another cohort of 15, who will receive the MSC transplantation after birth, and with historical controls. All children will be followed for 10 years, to see if those treated in utero and after fewer fractures, better bone density, improved growth and better quality of life.
"We are not aiming for a cure," warns Götherström. "It is not that they will raise a wheelchair and start running." Instead, she hopes to halve the number of fractures, which with the safety demonstration, is the objective of the test, make a big difference for patients and families. and just snatch a trial like this "could open a wider range of other conditions treated" before birth, she said.
in the US, the group of Mackenzie and another took a different approach: the treatment of fetus with blood stem cells taken from their mothers, the strategy it began exploring animals there are nearly a decade. last month, it filed an application with the US Food and Drug Administration to provide hematopoietic stem cells to the fetus with α-thalassemia, a severe form of the disease that is fatal before or shortly after birth. the prenatal cell therapy failed for thalassemia there nearly 30 years, but Mackenzie hopes a different outcome this time.
Because the cells come from the mother, she expects them to be better tolerated and infuse a much higher rate in the umbilical vein after gestation of 18 weeks. "If this process does not work, then we would go earlier," said Mackenzie, potentially injecting the cells into the fetal heart.
Alan Flake at the Philadelphia Children's Hospital (CHOP) in Pennsylvania is planning a similar trial of maternal stem cells in fetuses with sickle cell anemia, a painful debilitating disease that often reduces the life. (Flake led the transplant of fetal stem cells only known in the United States. made in the mid-190s on a fetus with severe immune deficiency, he has used stem cells from the donor by the father, and was considered largely successful.) Flake refused to speak with science citing a busy schedule and concerns about hyping a yet treatment in the trials, but in a video on the CHOP website he was optimistic. "the results of the research are absolutely convincing that we can achieve a healing sickle cell disease, "said Flake. The hospital raises millions of dollars to support a trial.
The medical risks of cell transplants in utero are generally considered modest, but include loss of pregnancy. Similar procedures such as fetal blood transfusions for anemia, are already available. But some fear the risk that may come after birth. "We rely on the idea that stem cells proliferate and differentiate into what we want," said David Chitayat, a medical geneticist at the Hospital for Sick Children in Toronto, Canada. Chitayat questions whether the proliferation may proceed unexpectedly, for example leading to tumors, a concern that cuts across many stem cell therapies. (Mackenzie notes that it should not be a problem for the strategy, because it plans to use the same type of cells than bone marrow transplants, which are not due to tumors.)
There are also concerns that the mother will be encompassed by the interests of the fetus, especially the fetal treatment programs are generally based in children's hospitals, and pediatricians consider the fetus their patient. "There is a person who has this uterus in her body" to be consulted, said Anne Drapkin Lyerly, a bioethicist at the University of Carolina North, Chapel Hill, who studied fetal surgery for spina bifida and other conditions. Any treatment will not only affect the fetus, but "the people who will be taking care of this baby," she said. Lyerly admits she does not know exactly how these concerns should be addressed beyond a particular attention to experience of the mother, including how it can react if the treatment results in pregnancy loss.
the doctors to conduct these tests are fully aware of the risks but emphasizes that the conditions they intended to treat cause suffering in life and often early death. If prenatal stem cell therapy is effective and safe, ethicists and other doctors agree, it could change lives. and as Chitayat rating, " if you do not start, you do not know. "
Sharing why he embraced cell therapy 14 years ago, when his wife was 7 months pregnant and the far field murkier it is today, Stefan Karlsson reached a response any parent can appreciate. "For us it was we see no disadvantages to try stem cells, there were only benefits," says. "And it might help to Olivia."
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