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21 Jun 2016 72 Comments

Catching em Young: Stem Cell Therapy To Treat Babies Inside the Womb

The University of Cologne, Germany is planning a clinical trial to treat babies inside the mother’s womb for a condition known as osteogenesis imperfecta (OI). It is debilitating genetic disease in which brittle bones break easily and often—from being jostled at school, or slipping on wet leaves outdoors or even from acrobatics in the womb.

The interesting and most inspiring aspect about this story is that, the trial is being heralded by 41 year old Oliver Semler, a paediatrician at the University of Cologne, who was himself afflicted by this condition. He had already fractured a pencil thin rib at the time of birth and had his second fracture at 2 days old. Despite the severity of the disease, Semler avoided life in a wheelchair, grew up to attend medical school and became a paediatrician.

The evolution of fetal stem cell therapy strategy:

Fetal stem cell therapy is not new. The technique has been tried since the 80’s. In those days, it was carried out on the premise that the immune system of the fetus is not completely developed and hence there would be lesser chances of rejection of the foreign cells by the fetus. A number of fetal stem cell therapies conducted across France and USA for conditions ranging from immune disorders to Thalassemia failed, as the cells were either rejected or because the engraftment did not happen. The interest in this field of research faded.

Again, in the late 2000s, certain discoveries provided some perspective to researchers. One, fetal T cells are able to reject foreign invaders and that maternal immune cells that are circulating through fetus also rebelled against donor cells.

A research group at University of California, San Francisco (UCSF) discovered that T Cells of the fetus are primed to convert into T-regulatory cells, which can tolerate outsiders, especially cells from the mother. So, the trick is to match the transplant to the mother to enable engraftment.

First Successes:

In 2002, an expectant couple in Sweden discovered that their fetus had OI, that too the most severe form, type III. They were referred to the Karolinska University Hospital in Stockholm. There, the researchers proposed a rather radical strategy of harvesting stem cells from the liver of aborted fetuses and infusing them through the umbilical vein into the fetus carried by Magdaleine (the pregnant mother). The stem cells used, mesenchymal stem cells (MSCs), are thought to elicit a less vigorous immune reaction than blood stem cells, and MSCs can develop into bone, along with other connective tissues. The hope was that MSCs would take hold and produce new, healthy bone. Even though the stem cells used were not a genetic match for the mother, some of them engrafted.  A bone biopsy done on the baby at 9 months after birth revealed that the donor cells mixed with those of the baby’s.

At first Olivia (the baby) did better than the doctors anticipated. But around her sixth birthday she began to deteriorate and suffered a spate of fractures. Eventually, Götherström and her colleagues retransplanted Olivia with more MSCs from the same donor tissue. Olivia’s fractures abated, and she has been retransplanted every 4 years since. Now 14 years old, she has not had a fracture in 18 months, surprising her doctors. Olivia’s father says she swims for physical therapy, enjoys sewing, arts and crafts, and, like most teenagers, shopping for clothes and spending time with her friends.

This success prompted Cecilia Götherström of Karolinska, the head of the therapy to carry out further treatments and laid the foundation for a clinical trial to actually determine if MSCs were indeed responsible for abating the condition and whether in utero therapy was making a difference.

The finishing piece of the jigsaw: OI Trial

Two years ago, Götherström and Semler met at a conference and that happened to mark the starting point for this clinical trial. The trial named BOOSTB4 is edging towards the starting line. Götherström,  Semler, and others have secured more than $9 million from the European Union and Swedish Research Council, and are crafting their protocol. Starting later this year, they hope to begin recruiting 15 families across Europe with fetuses shown by ultrasound and DNA testing to have severe OI and in the second or third trimester infuse them with MSCs from fetal liver cells, just like those Olivia received. The babies will receive additional infusions after birth. They’ll be compared with another cohort of 15, who will receive MSC transplants only after birth, and with historical controls. All the children will be followed for 10 years, to see whether those treated in utero and afterward have fewer fractures, better bone mineral density, better growth, and better quality of life.

“We are not aiming for a cure,” Götherström cautions. “It’s not that they will get up from a wheelchair and start running.” Rather, she hopes that halving the number of fractures, which, along with demonstrating safety, is the trial’s goal, will make a major difference to patients and families. And simply pulling off a trial like this one “could open up a wider field of other disorders being treated before birth”, she says. 

Other studies:

In the United States:

  1. Tippi Mackenzie’s group at University of California, San Francisco (UCSF) and others have an approach of treating fetuses with blood stem cells obtained from the mother. Mackenzie has filed a request with the FDA to offer haematopoietic stem cells to fetuses with alpha-thalassemia. 
  2. Alan Flake at The Children’s Hospital of Philadelphia (CHOP) in Pennsylvania is planning a similar clinical trial of maternal stem cells in fetuses with sickle cell anemia.

 

 

 

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