Each year thousands of children lose their lives as a result of neurological problems. They might recover with less intrusive procedures now.
Advanced therapies for the treatment of neurological disorders in young children may revolutionize prenatal care as we know it.
Michelle Johnson’s fourth pregnancy was going according to plan until the technician performing a routine 20-week ultrasound pushed against her pregnancy, which felt a little hard. The ultrasound was “very strange” and she kept asking questions as if she already had a baby, Johnson recalls. A few days later, he received a call from the department’s chief radiologist. In a low, sad voice, she told him that, unusually in her experience, Johnson’s baby had spina bifida and needed to see a fetal medicine specialist immediately.
Spina bifida is scientifically known as myelomeningocele and means that in children, the spinal cord that begins to grow when the tubular tube bends around the nerve does not completely fuse. This causes a superhighway nerve to leak into a small lump somewhere in the spinal cord. This congenital neurologic defect can lead to lifelong cognitive impairment, chronic movement disorders, and paralysis from the waist down.
“It was really overwhelming,” says Johnson, who was 35 at the time and lived in Portland, Oregon, USA. "It was shocking."
Approximately 1,400 babies are born with spinal deformities each year in the United States. The exact cause of this complex disease is unknown, but it is thought to involve a combination of genetic and environmental factors. For example, low folic acid intake during pregnancy and certain anticonvulsants have been associated with increased risk, but it is not clear what role these play.
Spinal cord injuries are usually treated 24 to 48 hours after birth. Surgeons sew the spinal cord back to the baby's body to prevent the condition from worsening. But when she called to schedule an appointment with a specialist, the nurse on call told Johnson about a new program in California that is using stem cells to treat children with spinal cord injuries in utero.
If he decides to participate, his son could become the second patient to receive such treatment. Johnson knew this was the chance she wanted to give her unborn child.
"It's like running a marathon," Johnson said, because the procedure must be performed before the 26th week of pregnancy. He set out on an ambitious mission following a battery of examinations, including blood testing and interviews.
I feel like I won the lottery - Michelle Johnson
Prenatal screening for psychiatric disorders has gradually increased in recent years. Technologies such as genetic analysis, neuroimaging and magnetic resonance imaging (MRI) allow doctors to visualize the development of the fetal nervous system and detect life-changing abnormalities early and repeatedly. Babies continue to grow throughout their lives, but most doctors can diagnose this growth process only after the baby leaves the womb. And a major part of brain development happens before a baby is born.
Now a new wave of pioneering neurological ovarian treatments is helping to change that. Before birth, basic tests are done to find possible surgical and medical treatments to correct the condition. pediatrician. Jeffrey Russ, a neuropsychologist at Duke University who recently wrote an article on intrauterine therapy, said the new medical field is "on the brink." The "next frontier" in neuroscience.
One of these behind-the-scenes trials is the first Food and Drug Administration (FDA)-approved trial for the treatment of spina bifida in utero. contains reproductive cells. The project, called Forensics, is the result of 25 years of work by surgeon Diana Lee Farmer of the University of California, Davis.
Intrauterine pelvic closure surgery has become the standard for critically ill patients. It slows down infections during pregnancy and, as Farmer's research has shown over the years, improves patient outcomes in the delivery area. . But the next effort aims to go beyond that. Neural tube grafts and grafts derived from stem cells called "mesenchymal stromal cells" were obtained and cultured for four days; if the cells multiply and reverse the damage. This happened during the search.
Bioengineer Aijun Wang, who developed the stem cell technology for the Cure study, said stem cells are "very smart." "Neurons can protect themselves from a deadly environment."
Preliminary data from a study in sheep with spina bifida suggests that the treatment allows them to walk without problems when their legs are weak. A similar situation was observed when the procedure was performed on Bulldog.
There were more than 30 people in the operating room, and Johnson was the second patient to undergo surgery in one day after 26 weeks of pregnancy. When inserted into the watermelon-shaped uterus, the uterus was completely removed from the body, allowing the fetus to nurse until delivery. This allowed doctors to access the herniated disc in the child's back and gently place the stem cell patch. Because this baby was so small, doctors operated with a special microscope.
Had it not been for treatment, Tobias would have been born. On February 1, 2022, he was delivered via C-section, weighing seven pounds, thirteen ounces (3.5 kilograms). Johnson said, "It seems like I received a jackpot."
Tobias will need to be monitored until he's 30 months old — his last solo visit this summer — and then the program's safety and effectiveness can be officially evaluated, thanks to the trial. Doctors are likely to monitor them for at least five years. At the time of writing, 10 more patients have received the CuRe treatment, and the Farmers team is investing $15 million ($12 million) to add 10 more to 29 patients. - Year. Farmers' team won't be able to analyze the data collected until 2028, and see if this new treatment can become a standard for children across the country.
The expectation is that it might help children who have spinal pain," Farmer stated. "Working the opposite hand like a successful science project, you solve one question and you unlock the door to another one."
"This is the basic science of surgically correctable conditions," Rush said. However, one limitation that allows in utero therapy to turn the tables on neurological conditions in infants is that therapeutic molecules or genes are not targeted. Rush said it's a "completely new approach" that will "break new ground."
Duke University colleagues are helping to develop an in-utero treatment protocol for Pompe disease, a rare genetic disorder that causes cells to store excessive amounts of sugar, leading to complications such as breathing and heart problems. and muscle weakness. Most patients die within a year or two of birth.
We hoped to change the paradigm when you can cure genetics - TP McKenzie
Pompe disease is caused by a deficiency of the enzyme alpha-glucosidase acid and is usually treated with enzyme replacement therapy (ERT), where children are regularly injected with this enzyme. However, as in the case of spina bifida, data show that starting ERT at birth improves symptoms but does not completely prevent disease progression.
So, when doctors at the Ottawa Hospital in Ontario, Canada, examined Ayla Bashir in February 2021, they discovered that she had inherited the same genes that led to her two siblings, Sara and Sara, being diagnosed with Pompe disease. They were born; They know they have to act quickly. At the ages of 29 and eight months, respectively, he and Sarah passed away. respectively. However, since Ayla was diagnosed in the womb, the medical team intervened faster.
On March 24, 2021, doctors administered the first dose of enzyme replacement therapy to Ayla, who was 24 weeks and 5 days pregnant. They inject a liquid medicine into the umbilical vein that contains a version of the missing alpha-glucosidase enzyme. This method ensures that the enzyme produced enters the bloodstream during fetal development. This means that the drug is not only foreign, but also does not cause a strong immune response that can occur during postpartum treatment. Six more payments every two weeks. Ayla was born on June 22, 2021, and has been receiving enzyme injections every week since then.
“Ayla is a very happy and active three-year-old girl who is meeting all her neurodevelopmental milestones,” said Karen Fong-Kee-Fong, a maternal-fetal medicine specialist who treated her at the Ottawa Hospital. “[I] watched the video of him jumping up and down.
As with Tobias, doctors will continue to monitor Ayla for at least five years to monitor the progression of the disease because the treatment does not fully prevent permanent organ damage. However, Ayla's story paves the way for prenatal treatment of such disorders with a simple injection.
“We hope to change the paradigm by which we can treat genetic diseases,” said Tibby McKenzie, one of the fetal surgeons at UCSF who led the development of the protocol used to treat Isla.
Different treatments are currently offered to newborns and will likely be offered at the fetal stage, McKenzie said. They conducted a five-year, 10-patient clinical trial in California to establish intrauterine ERT as an officially approved procedure for Pompe disease and other rare diseases such as neurological Gaucher disease, mucopolysaccharidosis, and Wolman disease. The study has already treated two children with mucopolysaccharidosis and "the news is positive," McKenzie said. At the ages of 29 and eight months, respectively, he and Sarah passed away. For the trial, which is available to patients worldwide, they are still accepting new participants.
Developing fetal treatments for these conditions would help raise awareness of the need to screen for genetic disorders in the first place, McKenzie said, "changing the equation" by enabling a virtuous cycle of more diagnoses and more treatment. Diagnosis and treatment, I call them yin and yang, they go together,” he said.
Although enzyme replacement is the least invasive form of treatment for genetic diseases and requires only a few doses over a patient's lifetime, the new technique could be used to edit fetal DNA for another hotly debated gene therapy. can be adjusted for cutting. replacing a child's gene or missing gene.
William Paranto, a professor of surgery at the Children's Hospital of Philadelphia, said McKenzie's work "lays the groundwork for such advanced treatments in the future." "If these trials can demonstrate the benefit of treating the disease with prenatal enzyme replacement therapy, the next question will be more specific treatments, such as gene editing in utero."
In a series of innovative experiments, Paranto used CRISPR genome editing techniques to modify the genetic code of certain mice in utero to treat genetic skin diseases, genetic lung diseases and genetic metabolic diseases affecting the lungs. lungs. Mouse liver
When it comes to predicting how long it will take to test gene-editing therapies in humans, the answer is always very difficult, and "it always takes longer than we want or expect," Paranto said. Probably about 5-10 years. -All you need to do is finish the task.
Today, as these experiences gain momentum, the ethical and practical implications of these advances must be considered.
"All of us truly require to start with specific instances where it's obvious the benefits surpass the risks," Rush added. It is clear that not all prenatal diseases can and should not be treated with stem cell, enzyme replacement and gene editing technologies.
And it is too early to have a clear picture of the long-term effects of intrauterine treatment. Most of the patients in this in utero trial are still infants or very young. We also have no long-term data on adult patients receiving gene editing therapy. While surgery and chemotherapy, like Farmer and McKenzie, are short-term procedures that doctors edit a baby's genetic code in the womb, these changes and their effects last forever.
Most importantly, intrauterine care is a unique double-risk procedure because it involves both the mother and her unborn child, Rush said.
More than a year later, the Johnsons returned to California. Johnson met other moms at the CuRe auditions, and hospital staff took turns welcoming Tobias and playing with him in the yard, bringing out cake and candles to celebrate his first birthday.
"It's really special," Johnson said. "Seeing everything they've done and meeting this miracle baby and seeing how healthy and happy he is, it just comes full circle."
At the time of writing, Tobias is over two years old and learning to walk.
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