Gene therapy brings hope to Danish girls, but the uncertainty is yet to come

Boston-Thomas Feldborg and Daria Rokina set out to explore the city almost every afternoon. They set off from a hotel near Charlestown, pushing a stroller, some days deep into the city center, others chose a path along the Charles River.
Every few minutes, Rokina would stop to take a peek inside and check the 16-month-old Alissa. She gently wiped Alissa’s cheek, muttered a few soothing words, made sure the little girl was warm enough in her yellow snow coat, and adjusted her glittering unicorn earmuffs.
Alissa has a better rest in the air outside. The daily walks relieved the couple some of the stress, because they didn’t know whether their daughter could survive-if so, under what conditions.
Feldberg, 50, has three eldest sons, while Rokina, 43, has one. Alissa is their first child, born on December 2, 2019 in Copenhagen, Denmark, where the family lives. During the first four months of life, Alissa looked normal. She learned to roll and sat up. She ba incessantly, grabbing the toy.
Then her progress began to stagnate. Six months ago, when Alissa didn’t want to crawl, Rokina took her to the pediatrician. The doctor assured her that the children were going forward at their own pace. That’s right
In eight months, this kind of trouble became not to be ignored. Alissa is hospitalized, dehydrated and unable to eat. A neurological examination revealed cherry-red spots on the back of her eyes. This is a devastating observation for the baby because it shows that it is one of the few genetic diseases, the deadliest and deadliest before the age of 5.
Feldberg immediately began a Google search. Before Alissa was diagnosed with Sandhoff’s disease (an extremely rare disease), he had accidentally discovered the idea of ​​gene therapy. If they can repair the defective gene that Alissa inherited from Romana and Rokina, she may suffer.
Internet research took the couple to the University of Massachusetts, where Alissa, then nearly 14 months old, became the world’s first child to receive a full dose of the new gene therapy in late January. If it works, it will trigger the cells in her brain to start producing the enzymes they lack, remove cell debris, and enable them to function normally.
Gene therapies like Alissa-decades of scientific vision-are finally becoming more common in the United States.
Dozens of diseases are currently being treated, although most diseases can only be resolved in clinical trials, such as Alissa’s. Experts say that in the next few years, gene therapy will soon be available for diseases that have never been effectively treated before, such as sickle cell disease, Huntington’s disease, ALS, Parkinson’s disease, certain forms of heart disease and many very different diseases. Rare diseases.
Dr. Cynthia Tift, director of the National Institutes of Health’s Pediatric Undiagnosed Diseases Program, said that the “exponential growth phase” of gene therapy has arrived.
Dr. Isaac Kohane, Dean of the Department of Biomedical Informatics at Harvard Medical School School of Medicine and Director of the Federal Government-funded Medical Research Center, said: “Finally, after decades of listening, we have witnessed some True success. Undiagnosed disease network.
Gene therapy provides the possibility of cure in the best case, and can truly reverse the root cause of the disease.
But, as simple as the idea seems—just correcting DNA typos—it is extremely difficult to turn into an actual treatment. So far, scientists have spent decades on each step of the process.
With such a new program aimed at life-long benefits, it is not yet known whether these methods will change the trajectory of children, allowing adults to live carefree lives or preventing the recurrence of the disease is still too early.
Kohane said: “People underestimate the ability to make gene therapy work in the short-term, but don’t have enough understanding of what changes will be brought about in the long-term.”
On December 2, 2020, her first birthday, Alissa received a colorful book and toys. She caught both and was very happy to be able to reach them.
But by the end of the month, she could no longer do that simple movement. She could barely raise her head and fell silent. The seizure subsided faster.
He and Rokina are completely alone, deciding whether to continue to treat Alissa. The other two babies had lower doses of gene therapy, but the procedures were similar, but the medical privacy law prohibited the couple from talking to their parents.
Tift said that for babies with Arissa’s disease and “cousin” disease, their quality of life is basically plant-based. Feeding tubes and other supportive care can keep them alive for a while. But they should all died in kindergarten.
Therefore, as Feldberg said, the two decided to “let hope overcome fear”. When they became one of the first families in history who could try something, it was simply too scary to see her decline.
But even if he and Rokina packed and boarded a plane to the United States in early January, they were still tortured by the idea that this therapy would only make Alissa live longer in the same tragic state.
Feldberg said while strolling through the park in the early spring afternoon: “Instead of such a cruel, short life span of two, three or four years, maybe she will only have a cruel, long life.” “This is it. What we worry about.”
On January 26, after several weeks of testing to ensure she was still a good candidate and preparing for surgery, Alissa was taken to the operating room at the UMass Memorial Medical Center near Worcester for brain surgery .
Researchers believe that the best way to unblock her brain cells is to inject gene therapy directly into her thalamus. The thalamus are two oval structures inside the brain, like the junction of a highway that connects many parts of the brain. . The doctor used an image-guided robotic arm to ensure it reached the correct position.
The next day, the same gene therapy was injected into the fluid around her spinal cord so that it could penetrate the nerves there.
If it goes according to plan, the added genes will direct her entire nervous system and brain cells to start producing the missing enzymes.
Dr. Pavan Cheruvu, CEO of Sio Gene Therapies, a New York-based biotechnology company, said: “In fact, you don’t need a lot of enzyme activity to make neurons function better.” Alyssa’s treatment and her parents U.S. stay
A previous child underwent thalamic surgery, but there were not enough treatments to give her a full dose. Dr. Terence Flotte, dean of the UMass School of Medicine, said that so far, her condition has been stable when most children with the disease have the disease. The other child received a spinal injection, but not thalamus.
Alissa was the first person to receive full-dose treatment in both locations. Patients in future trials will receive higher doses. Feldborg and Rokina hope that Alissa will make a profound and positive change in her life.
About 45 minutes west of Boston, a group of Jacob sheep lives in a series of enclosures overlooking the rolling hills.
Protected by their humpbacks and electric fences, they are far away from the coyotes, and a few sheep stopped to stare at the stranger at the Cummings School of Veterinary Medicine at Tufts University where they lived. Then they bolted it.
The 110 sheep are the offspring of a pair of sheep that once lived on a farm in Texas. In 1999, two lambs began to stumble and stumble. They died of seizures, lost their eyesight, and had difficulty swallowing. The owners Fred and Joan Horak wanted to understand why.
It took ten years for researchers from the New York University Medical Center (now the New York University Langone School of Health) to discover that genetic mutations in sheep also caused Ty-Sachs disease. Researchers later learned that cats can also inherit similar genetic mutations.
Research Professor Douglas Martin of Auburn University School of Veterinary Medicine in Alabama said that finding an animal model of a naturally occurring disease is very helpful in developing treatments.
In animals, the researchers tested and refined the virus that ultimately provided Alissa’s gene therapy.
Gene therapy is usually transported into cells via a virus, which is similar to the pathogen used in the COVID-19 vaccine produced by Johnson & Johnson and AstraZeneca-Oxford University. It has taken decades to find the right virus and modify it to safely deliver genes or editing tools.
In Alissa’s experiment, the virus carried DNA instructions to make the missing enzyme. The drug was designed by Miguel Sena-Esteves, a researcher at the University of Massachusetts Medical School in Massachusetts. The research has been carried out for more than ten years. Even if Alissa is missing only one gene, the therapy can provide two genes. Animal studies have shown that adding both the gene that causes Tay-Sachs and the nearby gene that causes Sandhoff has the best effect for children who suffer from both conditions.
Although other gene therapies rely on gene editing to change the cell’s DNA code, Alissa’s own DNA has not been changed in this way.
Flott said that her immune system is suppressed by the drug, so if needed, she can be dosed again with virus-carrying gene therapy.
Researchers have previously tried to treat these two diseases by providing the missing enzyme instead of adding genes, but it is too large to enter the brain from the bloodstream.
By 2012, Sena-Esteves had proved that this virus and gene therapy were effective in mice; Martin at Auburn University proved the same in cats. The third colleague, Now Heather Gray-Edwards of the University of Massachusetts Medical School used it to save Jacob Sheep.
Before attempting to use this method on children, the research team decided to test it in monkeys. After the success of other animals, the US Food and Drug Administration may not need it, but they have to be extra careful.
The result is devastating. Edwards said that these monkeys became cold and lost flexibility. They obviously didn’t help.
After years of research, people have discovered that animals have gained too many benefits: the extra enzymes that help clean up the brain cells of other mammals are overwhelmed and killed monkey cells.
Sena-Esteves said that the day he learned of the results may be the worst day of his career. However, it is much better to learn a lesson about monkeys.
Carefully adjusted the treatment methods for children, in order to achieve the “Goldilocks” balance: not too little, but not too much.
Last year, Feldborg and Rokina are now taking paid vacations for their sales and logistics work, befriending the Danish family whose two other babies were diagnosed with Sanderhof.
One child is two months older than Alissa and the other is eight months old. None of them received gene therapy. Both died earlier this year.
The doctor chose Alissa for the experiment, hoping that she was still young, and the recent loss was enough to make her brain damage reversible.
Dr. Florian Eichler, a pediatric neurologist at Massachusetts General Hospital, said: “Many cells are simply under stress due to the toxic accumulation of fat.” “If we can properly return healthy copies of the gene and enzyme, then the cell can recover.”
Last fall, Feldberg and Rokina watched their daughter slip further. They worried that Alisa had lost too much function and was therefore disqualified from participating in the trial, otherwise the treatment would come too late and there would be nothing. effect.
The doctor warned them not to expect too much. No one knows whether this therapy will help, or how long it may take to start observing changes.
But a week after the operation, Alissa’s shiny blue eyes were rolling steadily, seeming to stabilize and concentrate. Her eyes kept moving and she couldn’t see much.
In February, Alissa began to move her hands intentionally and started eating more. Swallowing is a skill she has not lost, but maybe because steroids are part of her care, she is hungry again and accepts a spoonful of soft food. Recently, she learned how to suck a bottle for the first time.
There is also a wonderful surprise. About two weeks after the operation, Alyssa began to smile again. Not a response to the outside world, but a response to inner pleasure or humor.
A few days later, she laughed deep in the belly. Feldberg said he can count on her to laugh like this number of times before the operation. But in the past few weeks, she laughed in private almost every day.
When it first happened, Feldberg said while bathing her: “We are very happy, we kiss each other, just like we have become the world champions of our favorite sport.”
To make up for her lack of vision and hearing, Rokina and Feldborg tried to provide Alissa with some connection to the world through touch.
Rokina is Russian and grew up in the tradition of massaging babies. Before Alissa’s gene therapy, months of massage and exercise therapy did almost nothing, just let her continue to swallow.
After the operation, Feldberg and Rokina changed their practices and drove Alissa to a remote Boston suburb for baby massage once a week, and went to the nearby Aling two or three days a week in the morning. In the town of Dayton, Matty Wilkinson is trying to re-establish contact here. The little girl’s brain is powerless to her body.
Wilkinson has a master’s degree in child development and has been trained in the Feldenkrais method and the Anat Baniel method for children. She teaches Alissa’s brain through small movements to perceive her neck, arms, legs, pelvis and spine again.
He said after a recent meeting: “She must rebuild her map and how to interact with the environment.” “I’m trying to make the information clearer and clearer so that she can perceive these feelings and get more choices. ”
Wilkinson lay next to Alyssa, gently stroking his left shoulder while stroking the back of the same shoulder. She would occasionally move her mouth by sucking, but otherwise would remain still.
One of the earliest successful gene therapies was a treatment for spinal muscular atrophy. The results showed that although this therapy is very effective, it is not enough to rely on this therapy alone. Just as newborns learn to control their limbs by moving their limbs, children whose brains have lost the ability to guide movement (or children who have not developed movement in the first place) also need to practice to form the correct wiring.
Eichler said: “We say that the nervous system must use it, otherwise it will lose it.” “It must be continuously stimulated and active, so Alisha’s parents are crucial to everything she does well. important.”
People told Feldborg how “brave” he and his wife were about trying gene therapy with Alissa. He was not sure how to respond.
He said: “There is a good line between bravery and stupidity.” “Are we so stupid about hope? Is this the foolish task we are performing?”
In the last week after three months of surgery, doctors began to perform a series of tests on Alissa to see if they could find objective signs of progress. They hope to see evidence in her MRI scan that her brain is repairing itself.
Tift of the National Institutes of Health said that if the trial achieves any of the three possible results, it will be considered a success: This may slow Alyssa’s decline and prevent it from falling further. Or actually help her acquire skills.
Tiff said: “None of these children can make progress on their own. They just don’t make progress.” “In a disease that only progresses downhill, even maintaining function is a victory.”
No matter what happens, the trial represents a “great milestone” in the treatment of Sandhoff and related diseases, Eichler said.
Tay-Sachs has been discovered for more than a century. At least half of the time, people learned about it and Sandhoff’s chemical reaction to the brain. Now, the genetic defect itself can finally be resolved, Eichler said.
Nevertheless, there is still a lot of knowledge about the best time to treat, which cells need to be targeted and what meaningful changes occur.
Eichler said: “This is the essence of progress. If we know what works, then we don’t need to experiment.” “I feel for my parents.”
Feldberg and Rokina said they hope the trial will help others, but they are realistic about what they can achieve. They knew that Alissa would never be like other children. They just want a daughter with whom they can communicate in some way.
Feldberg said: “She can sit in a wheelchair or anything else, but if we don’t think from this perspective, then I think we might be more stupid than brave.”
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Post time: Apr-26-2021