Groundbreaking clinical trial aims to treat spina bifida before birth

Groundbreaking clinical trial aims to treat spina bifida before birth

Three babies have been born after receiving the world's first spina bifida treatment combining surgery with stem cells. This was made possible by a landmark clinical trial at UC Davis Health.

The unique treatment, performed while a fetus is still developing in the womb, could improve outcomes for children with this birth defect.

The clinical trial, which started in spring 2021, is officially known as the “CuRe Trial: Cellular Therapy for In Utero Repair of Myelomeningocele.” A total of 35 patients are being treated.

The three babies born so far in the study will be monitored by the research team until they are 30 months old to fully assess the safety and effectiveness of the procedure.

The first phase of the study is funded by a $9 million federal grant from the state stem cell agency, the California Institute for Regenerative Medicine (CIRM).

“This clinical trial could improve the quality of life for so many future patients,” said Emily, the first clinical trial participant who traveled from Austin, Texas to take part. Their daughter Robbie was born last October. "We didn't know about spina bifida until we were diagnosed. We are so grateful that we were able to be a part of it. We are giving our daughter the very best chance for a bright future."

Spina bifida, also known as myelomeningocele, occurs when the spinal cord tissue fails to fuse properly in the early stages of pregnancy. The birth defect can cause a range of lifelong cognitive, mobility, urinary and bowel disabilities. It affects 1,500 to 2,000 children in the United States each year. It is often diagnosed through ultrasound.

While surgery performed after birth can help reduce some of the effects, surgery before birth can prevent or reduce the severity of spinal damage to the fetus, which worsens over the course of pregnancy.

“I have been working toward this day for nearly 25 years,” said Diana Farmer, the world’s first female fetal surgeon, professor and chair of surgery at UC Davis Health and principal investigator of the study.

The path to a future cure

As leader of the Management of Myelomeningocele Study (MOMS) clinical trial in the early 2000s, Farmer had previously helped prove that fetal surgery reduced neurological deficits caused by spina bifida. Many children in this study showed improvement but still required wheelchairs or leg braces.

Farmer specifically recruited bioengineer Aijun Wang to take this work to the next level. Together they founded the UC Davis Health Surgical Bioengineering Laboratory to find ways to use stem cells and bioengineering to improve surgical effectiveness and improve outcomes. Farmer also founded the UC Davis Fetal Care and Treatment Center with fetal surgeon Shinjiro Hirose and the UC Davis Children's Surgery Center several years ago.

Farmer, Wang and their research team have been working on their novel approach to using stem cells in fetal surgery for more than 10 years. Over this time, animal models have demonstrated its ability to prevent the paralysis associated with spina bifida.

The stem cells are believed to help repair and restore damaged spinal tissue beyond what surgery alone can achieve.

Preliminary work by Farmer and Wang proved that prenatal surgery combined with human placental mesenchymal stromal cells held in place with a scaffold of biomaterial to form a "patch" helped lambs with spina bifida walk without noticeable disability.

When the baby sheep that received stem cells were born, they were able to stand and walk around almost normally at birth. It was wonderful.”

Aijun Wang, bioengineer

As the team refined their surgical and stem cell technique for dogs, the treatment also improved mobility in dogs with naturally occurring spina bifida.

A pair of English bulldogs named Darla and Spanky were the first dogs in the world to be successfully treated with surgery and stem cells. Spina bifida, a common birth defect in this breed, often leaves them with little function in their hindquarters.

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At their re-examination after surgery at 4 months of age, Darla and Spanky were able to walk, run, and play.

The world's first human process

When Emily and her husband Harry found out they were becoming parents for the first time, they never expected pregnancy complications. But the day Emily learned her developing child had spina bifida was also the day she first heard about the CuRe study.

For Emily, it was a lifeline they couldn't refuse.

Participating in the study would mean she would have to temporarily move to Sacramento for fetal surgery and then weekly follow-up visits throughout her pregnancy.

After screenings, MRI scans and interviews, Emily received the life-changing news that she had been accepted into the study. Her fetal surgery was scheduled for July 12, 2021, at 25 weeks and five days of pregnancy.

Farmer and Wang's team is producing clinical-grade stem cells - mesenchymal stem cells - from placental tissue at UC Davis Health's CIRM-funded Institute for Regenerative Cures. The cells are known to be among the most promising cell types in regenerative medicine.

The laboratory is a Good Manufacturing Practice (GMP) laboratory for safe human use. This is where they made the stem cell patch for Emily's fetal surgery.

"It's a four-day process to make the stem cell patch," said Priya Kumar, the scientist at the Center for Surgical Bioengineering in the Department of Surgery, who leads the team that makes the stem cell patches and delivers them to the operating room. “The time we pull out the cells, the time we seed onto the scaffold, and the time we deliver are all crucial.”

A first in the history of medicine

During Emily's historic procedure, a 40-member surgical and cell prep team performed the careful dance they had long prepared for.

After Emily was put under general anesthesia, a small opening was made in her uterus and they allowed the fetus to swim to this intersection so they could expose its spine and spina bifida defect. Surgeons used a microscope to carefully begin the repair.

Then the moment of truth: the stem cell patch was placed directly over the exposed spinal cord of the fetus. Fetal surgeons then closed the incision to allow the tissue to regenerate.

"The insertion of the stem cell patch went smoothly. Mother and fetus did great!" Farmer said.

The team declared the first operation of its kind a success.

Delivery day

On September 20, 2021, at 35 weeks and five days of pregnancy, Robbie was born via cesarean section weighing 5 pounds, 10 ounces and measuring 19 inches long.

"One of my first fears was that I wouldn't be able to see her, but they brought her to me. I could see her toes wiggling for the first time. It was so calming and a little out of this world," Emily said.

For Farmer, this day is what she has long hoped for, and it brought surprises. If Robbie had been left untreated, she would have been born with leg paralysis.

"It was very clear from the minute she was born that she was kicking her legs, and I remember very clearly saying, 'Oh my God, I think she's wiggling her toes!'" said Farmer, who noted that the observation wasn't an official confirmation, but it was promising. "It was amazing. We kept saying, 'Am I seeing this? Is this real?'"

Mom and baby are home and doing well. Robbie just celebrated her first birthday.

The CuRe team is cautious about drawing conclusions and says there is still a lot to be learned in this safety phase of the study. The team will continue to monitor Robbie and the other babies in the study until they are 6 years old, with a key assessment at 30 months to see if they are walking and potty training.

"This experience was overwhelming and exceeded all expectations. I hope this study will improve the quality of life for so many future patients," said Emily. “We are honored to be part of the story.”

Source:

University of California-Davis Health

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