Stem cells and birth defects: Could gastroschisis be treated in utero?

gastroschisis birth defects
Although Gianna was treated surgically, Dario Fauza, MD, hopes to someday use stem cells from the amniotic fluid, multiplied and returned to the womb, to naturally heal gastroschisis and other birth defects. (Courtesy Danielle DeCarlo)

Except when spreading awareness about her condition, 6-year-old Gianna DeCarlo prefers not to wear two-piece bathing suits because of the long vertical scar on her stomach. “Even though nobody’s said anything, she feels like she’ll be made fun of,” says her mother, Danielle. “I do what I can to make her love her body.”

Gianna doesn’t remember her three surgeries or the nasogastric tube she needed as an infant, before she was able to eat normally. She was born with gastroschisis, a striking birth defect in which the abdominal wall doesn’t seal fully during fetal development. As a result, her intestines developed outside her body. She was fed through an IV for several weeks, and was finally stitched fully shut at age 2.

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Gastroschisis (CDC illustration/Wikimedia Commons)

For reasons that aren’t known, gastroschisis is on the rise. According to CDC data, its prevalence has increased 30 percent between 2006 and 2012, from 3.6 to 4.9 cases per 10,000 births.

Gianna is now doing fine — an active, healthy eater who dances and does gymnastics. But some infants with gastroschisis have long-term problems with feeding, digestion and absorption: the intestines may remain thickened and mildly inflamed after surgery, likely from having been exposed to amniotic fluid in the womb.

“Some infants get repaired and get home relatively quickly, whereas others are on IV nutrition for months to years,” says Christopher Duggan, MD, MPH, Gianna’s physician at the Center for Advanced Intestinal Rehabilitation at Boston Children’s Hospital.

In many cases, like Gianna’s, gastroschisis is first discovered during a routine prenatal ultrasound. What if babies could be treated before birth to avoid intestinal damage? Recent research shows that the necessary ingredients are already there: they’re floating in the amniotic fluid.

Stem cell therapy in utero?

For more than a decade, Dario Fauza, MD, PhD, a pediatric surgeon at Boston Children’s, has isolated mesenchymal stem cells from the amniotic fluid — so-called afMSCs — and distilled them to high concentrations, aiming to use them to repair birth defects.

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Gianna before her gastroschisis was closed up. (Courtesy Danielle DeCarlo)

afMSCs are one step more specialized than pluripotent stem cells. They give rise to a variety of tissues, including muscle, cartilage and bone. Fauza’s original idea was to use them to build tissue-engineered patches to repair defects such as congenital diaphragmatic hernia, airway abnormalities, and certain bone defects. But gradually, the idea expanded to what he calls Trans-Amniotic Stem Cell Therapy, or TRASCET.

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afMSCs in culture (courtesy Fauza lab)

Fauza discovered the natural biological role of afMSCs in 2011, showing that they significantly enhance the ability of fetuses to repair tissue damage in utero in a large animal model. To harness that natural role for therapeutic purposes, Fauza and colleagues have been expanding afMSCs in the laboratory, perfecting the manufacturing process and seeing promising benefits in animal models of spina bifida and abdominal wall defects, including gastroschisis, with others in the works.

In a rat model of gastroschisis, Fauza and colleagues, recently showed that injections of labeled, concentrated afMSCs significantly mitigated bowel damage as compared with no treatment or a simple saline injection. Last month, reporting at the annual meeting of the American Pediatric Surgical Association in San Diego (May 14-17), the team confirmed these results in a rabbit model, earning them an award from the International Fetal Medicine and Surgery Society — the ninth received to date for different facets of TRASCET.

Duggan finds a lot of hope in Fauza’s findings. “This could be a very big deal,” he says. “The theory is, the sooner you repair, the more time the bowel has to develop normally.”

Getting regulatory approval

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afMSCs are readily available in the amniotic fluid drawn during routine amniocentesis.

More needs to be understood about how the afMSCs worked — they may heal through secreted factors, rather than (or in addition to) engrafting themselves into tissues. But the beauty of the TRASCET approach is that afMSCs are the baby’s own cells, readily obtained during a standard prenatal amniocentesis, performing the same role that they already perform in nature. Fauza is simply returning them to their original environment, in more concentrated amounts.

Another advantage of TRASCET is the fact that it does not require the use of scaffolds, as in the classic tissue engineering approach.

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Fauza

“This should facilitate FDA approval of clinical trials,” says Fauza, whose goal is eventually obtaining such approvals. “With TRASCET, we are essentially boosting a natural process, with potentially multiple clinical applications and in a minimally invasive fashion. Both the harvesting and the injection of the afMSCs are outpatient procedures, so TRASCET could become a very practical and easily accessible strategy for different birth defects.”

In many case, engineered tissue will still be required, Fauza notes. “This of course demands surgery and different scaffolds for the engineering of grafts, all of which carry very different levels of risk and of regulatory intervention when compared with TRASCET,” he says. “TRASCET should be applicable to a much larger population.”

Learn more about Fauza’s research and the Center for Advanced Intestinal Rehabilitation.