The disease took Zara, then Sara. Could Ayla be saved?

1. The Disease
Ayla Bashir, who was treated while in utero for Pompe disease, in the gardens at the Children’s Hospital of Eastern Ontario in Ottawa on September 8, 2022. Pompe disease is a genetic disorder that could be fatal within the first year of life and killed two of her sisters. (Photo: NYTimes)
For the first time, doctors have successfully treated a fetus by infusing a crucial enzyme into its minuscule umbilical cord, halting an otherwise fatal inherited disorder known as severe infantile Pompe disease.اضافة اعلان

The baby, Ayla Bashir, now 16 months old, is developing normally, giggling, and babbling and toddling in her home in Ottawa, Ontario.

Behind the result of Ayla’s treatment, published last week in the New England Journal of Medicine, is a medical drama featuring passionate researchers at three medical centers and the doctors who were moved by the family’s plight.

The hope — and expectation — is that this family’s experience may pave the way for fetal treatments that alter the course of a variety of severe genetic diseases, including hemophilia and spinal muscular atrophy, and obviate the need for lifelong medical care.

In keeping with the goal, the group reported that since they submitted their results for publication, a fetus was treated with enzymes for another disease, Hunter’s syndrome, before birth. He was born October 27, and doctors have continued monitoring his condition.

Ayla — the doctors’ first success — has severe infantile Pompe, a genetic disorder that can be fatal in the first year of life. She is her parents’ fifth child, but only the third to survive. The other two, Zara and Sara, died of the disease, and their parents, Sobia Qureshi and Zahid Bashir, watched as it progressively weakened their babies’ muscles, robbing them of their ability to move until, unable to swallow, unable to breathe and with heart muscles so thickened that their hearts were unable to pump, they died.

The idea for the treatment that saved Ayla began with Dr Tippi MacKenzie, a pediatric surgeon at the University of California, San Francisco. She and her team had previously treated fetuses with thalassemia, a genetic disease caused by lack of hemoglobin. Those fetuses received blood transfusions and a stem cell transplant by inserting a needle into their umbilical cords and supplying fresh blood.

That gave her an idea. There are rare genetic conditions known as lysosomal storage diseases, in which a missing enzyme leads to an accumulation of toxic substances in cells. A few of these diseases — including severe infantile Pompe — can be treated by infusing the missing enzyme starting immediately after birth. But as irreversible damage can start before birth, MacKenzie wondered if she could treat fetuses with these diseases by infusing enzymes through the umbilical cord into their bloodstream.

She tried it with mice that had one of the diseases known as Mucopolysaccharidosis type VII, or MPS7. In its most severe form, it results in a condition known as hydrops fetalis, characterized by a fatal accumulation of fluid in the body.

“The mice did really, really well,” she said.

Then, in 2019, a woman whose unborn baby had severe MPS7 was referred to MacKenzie. The Food and Drug Administration gave MacKenzie permission to try infusing the enzyme before birth; unfortunately, by the time the procedure was approved, the disease was so far advanced that MacKenzie decided not to do it. The baby was stillborn.

The FDA then suggested MacKenzie propose a clinical trial that would include any fetuses with severe lysosomal storage diseases with an approved enzyme replacement. The handful of diseases in question are very rare. Just six or seven babies are born with severe infantile Pompe disease in the United States each year.

Once MacKenzie got FDA approval in 2020, she waited for referrals of pregnant women whose fetuses had lysosomal storage diseases.

Qureshi was the first.

She and Bashir had always wanted children — at least three. When they married in 2008, they assumed they would have a growing family. Qureshi, 37, is from Pakistan and Bashir, 41, is from Canada. Their families knew each other. Theirs was an arranged marriage with a simple traditional ceremony in Pakistan, the couple said.

When Qureshi became pregnant in 2010, they had no idea what was to come.

The couple’s first baby with severe Pompe disease, Zara, was born in 2011. When she was five months old, Qureshi and Bashir were referred to Dr Pranesh Chakraborty, a pediatrician at the Children’s Hospital of Eastern Ontario and a specialist in inherited metabolic disorders.

The enzyme treatment involved infusing babies with the missing enzyme — acid alpha-glucosidase — every two weeks, along with drugs to suppress their immune systems so they did not develop antibodies that would destroy the enzyme.

Chakraborty wanted to start treating Zara, but the day she was supposed to get her first infusion, her lungs collapsed, and she spent a month in intensive care, including 10 days on a ventilator. During that time, she lost all movement in her legs, and her ability to swallow deteriorated so much that she needed a feeding tube to eat.

She started the enzyme treatment when she was six-and-a-half months old, but her disease progressed.

When Zara was two years old, her parents made the difficult decision to stop treatment and provide only palliative care. She died peacefully at home five months later.

Chakraborty, whose own daughter was born four days after Zara, could not help noticing the heartbreaking contrast.

In 2016, Qureshi was pregnant again. Prenatal testing revealed severe Pompe once again. Bashir and Qureshi decided to forgo enzyme therapy for their baby Sara and to provide only palliative treatment.

“It was a very, very tough decision,” Qureshi said. “But there was no hope out there, and we did not want her to suffer.”

Sara died when she was 8 months old.

In early February 2020, Chakraborty got a call from Qureshi. She was pregnant again, and a prenatal test indicated that that fetus, too, had severe Pompe disease. Qureshi and Bashir had decided that they wanted to treat this fetus, hoping treatment had improved and that even if after childbirth the baby could not be saved, perhaps her suffering would be less.

That evening, Chakraborty called a researcher at Duke University, Dr Priya Kishnani, who had developed the enzyme replacement and immunosuppression treatment, asking for advice on how to proceed.

“What I wanted to do was to organize the options,” Chakraborty said. “What’s new? What can we do?”

Kishnani had made finding a way to treat lysosomal storage diseases her mission in 1991, when she was still a medical trainee. There are milder forms of the diseases, in which patients can have no symptoms for years or even decades before their hearts and muscles eventually weaken and they develop serious health problems that require ongoing enzyme infusions. But in the cases Kishnani saw, the outcomes were tragic.

She and her colleagues embarked on a bid to find a treatment and, a decade later, they were ready to try treating babies after they were born by injecting the missing enzyme.

But when they first tried the treatment, two of the three babies did not survive. The reason, the researchers discovered, was that children had a severe form of the disease — their bodies made none of the enzyme. And when they injected the enzyme, the babies’ immune systems saw it as foreign and made antibodies that destroyed it.

Perhaps if they suppressed the babies’ immune systems, the enzymes would be able to work.

She began a study at Duke that enrolled babies from around the world, giving them a five-week course of immunosuppression and regular enzyme infusions.

“It works,” she said triumphantly. After treating about 70 babies, she could say with confidence that she found a way to help. The children are still alive — the oldest is about 12 — but often have muscle weakness.

When Chakraborty called Kishnani about Qureshi’s latest pregnancy, she told him there might be a way to prevent all the consequences of infantile Pompe. A new clinical trial was about to start. MacKenzie, in collaboration with her group at Duke, including an associate, Dr Jennifer Cohen, were going to try providing the missing enzyme before a baby was born. It was not possible to get the immunosuppressant drugs into the fetus’s circulation, but the fetus would not be making antibodies yet. So, the researchers said, immune suppression could start after birth and would be discontinued after the babies grew to tolerate the enzymes.

Soon, Chakraborty, Kishnani, MacKenzie, and Cohen were trying to organize a way to deliver the treatment. If Qureshi were to enroll in MacKenzie’s trial, she would have to go to San Francisco for the infusions. And there were risks, most notably that the infusions could precipitate a premature delivery.

Qureshi and Bashir were willing to take that risk, but the coronavirus pandemic got in the way, adding impossible complications with travel restrictions and quarantines.

“It was a very hard decision. I was grieving, but I told the doctors, ‘I don’t think I can go to San Francisco’,” she said.

Her doctor, Dr Karen Fung-Kee-Fung, a maternal-fetal medicine specialist and professor of obstetrics and gynecology at the Ottawa Hospital, understood. “In the end, the barriers were insurmountable,” she said.

The only feasible option was to treat Ayla in Canada, but the clinical trial authorization was for MacKenzie’s group in San Francisco. The doctors in Ontario needed permission from their hospital to try the treatment as an off-label drug infusion that was not part of a clinical trial.

Then, they had to get the enzyme from the biotech company Sanofi Genzyme of Canada. It was approved for treating babies, but the doctors wanted to treat a fetus, and the company had to be convinced that the drug could be used.

After permission was granted, the Ottawa doctors infused the drug into the fetus’s umbilical cord six times from weeks 24 to 36 of gestation. All indications were that Ayla was developing normally. Her heart muscle was not growing thick, as it had in her siblings who had died. She was moving normally and was practicing breathing, as is expected with a healthy fetus.

The doctors delivered Ayla on June 22, 2021, “a sweet, juicy baby”, Fung-Kee-Fung said.

At first, everything was a question mark for her parents — would she be able to hold up her head? Would she be able to crawl, to walk?

She could — and right on time.

“Now, I am not cautiously optimistic, but almost scarily optimistic,” Bashir said.

Qureshi breathed a sigh of relief.

“We are very, very fortunate and so thankful,” she said, adding that she and her husband do not plan to have any more children.

“We’ve had our fair share of adventure,” Qureshi said.

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