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Gene therapy offers hope for Danish girl, but uncertainty lies ahead

BOSTON — Thomas Feldborg and Daria Rokina set off nearly every afternoon to explore this city. They leave from their hotel in the Charlestown neighborhood, pushing their baby carriage, some days heading deep into downtown, others choosing a path along the Charles River. 

Every few minutes, Rokina stops to peek inside and check on 16-month-old Alissa. She gently rubs Alissa's cheek and coos a few soothing words, making sure the little girl is warm enough in her yellow snowsuit and adjusting her sparkly unicorn earmuffs. 

Alissa rests better in the outside air. The daily walks allow the couple to relieve some of the stress of not knowing whether their daughter will survive – and if so, in what condition.

Feldborg, 50, has three older sons, and Rokina, 43, has one. Alissa, their first child together, was born Dec. 2, 2019, in Copenhagen, Denmark, where the family lives. For her first four months of life, Alissa seemed perfectly normal. She learned to roll and sit up. She babbled and grabbed for toys. 

Then her progress began to stall. By six months when Alissa wasn't trying to crawl, Rokina took her to the pediatrician. Children advance at their own pace, the doctor assured her. Nothing was wrong.

At eight months, the trouble became impossible to ignore. Alissa was hospitalized, dehydrated and unable to eat. A neurological exam turned up cherry red spots at the back of her eyes, a devastating observation in a baby, because it indicates one of a few genetic disorders, most terrible and deadly before age 5.

16 month old Alissa gets gene therapy in a fight for her life.

16 month old Alissa Feldborg is undergoing gene therapy for Sandhoff disease, a very rare, fatal genetic disorder.

Robert Deutsch, USA TODAY

Feldborg immediately started Googling. Before Alissa received the diagnosis of Sandhoff disease, an extremely rare condition, he already had stumbled across the idea of gene therapy. If they could just repair the faulty gene Alissa inherited from him and Rokina, she might have a shot at life.  

That internet research led the couple to the University of Massachusetts, where in late January, Alissa, then nearly 14 months old, became the first child in the world to receive a full dose of a new gene therapy. If it worked, it would trigger the cells in her brain to start making the enzyme they had been missing, clearing out cellular debris, so they can function normally.  

CHOOSING HOPE

The first in an occasional series exploring how scientific advances are transforming care for rare diseases.

Gene therapy like Alissa's – a scientific vision for decades – is finally becoming a more common reality in the United States.

Dozens of disorders are now being treated, though most still only in clinical trials, like Alissa's. Within the next few years, experts say, gene therapies could soon be available for conditions never effectively treatable before, such as sickle cell disease, Huntington's, ALS, Parkinson's, some forms of heart disease and a host of very rare diseases. 

"The exponential growth phase" of gene therapy has arrived, said Dr. Cynthia Tifft, director of the Pediatric Undiagnosed Diseases Program at the National Institutes of Health.

"Finally, after literally decades of hearing it was just around the corner, we are witnessing some real successes," said Dr. Isaac Kohane, chair of the Department of Biomedical Informatics at Harvard Medical School and head of the federally funded Coordinating Center for the Undiagnosed Diseases Network.

to figure out the sheep carried the same genetic mutation that causes Tay-Sachs disease. Researchers later learned cats also can inherit a similar genetic mutation.

Finding an animal model in which a disease naturally occurs is extremely helpful for developing treatments, said Douglas Martin, a professor at the Auburn University College of Veterinary Medicine in Alabama who studies these conditions in house cats. 

In animals, researchers tested and refined the virus that eventually delivered Alissa's gene therapy.

Stephanie Bertrand, assistant farm manager at Cummings School Farm at Cummings School of Veterinary Medicine at Tufts University, provides care for the Jacob sheep that are integral to the research being led by University of Massachusetts Medical School. Photo credit: Matthew Healey for Tufts University.

Stephanie Bertrand, assistant farm manager at Cummings School Farm at Cummings School of Veterinary Medicine at Tufts University, provides care for the Jacob sheep that are integral to the research being led by University of Massachusetts Medical School. Photo credit: Matthew Healey for Tufts University.
Matthew Healey, Matthew Healey for Tufts University

Gene therapies are often transported into cells by viruses – similar to how pathogens are used to deliver the COVID-19 vaccines made by Johnson & Johnson and AstraZeneca-Oxford University. It's taken decades to find the appropriate viruses and engineer them to safely deliver genes or editing tools.  

In Alissa's trial, a virus carries DNA instructions for making the missing enzyme. Designed by Miguel Sena-Esteves, a UMass Medical School researcher who has been working on the project for more than a decade, the therapy delivers two genes, even though Alissa is only missing one. Animal studies showed that adding both the gene that causes Tay-Sachs plus a nearby one that causes Sandhoff provides the best results for children with both conditions.

Alissa's own DNA isn't changed in this approach, though other gene therapies rely on gene editing to alter cells' DNA code. 

Her immune system is kept tamped down with medication so that, if needed, she can be dosed again with the virus-carrying gene therapy, Flotte said.

Lena Labdi, a research assistant at the University of Massachusetts Medical School, examining slides in the Sena-Esteves lab on April 13, 2021 Arlington, Mass.

Lena Labdi, a research assistant at the University of Massachusetts Medical School, examining slides in the Sena-Esteves lab on April 13, 2021 Arlington, Mass.
Robert Deutsch, USA TODAY

Researchers have tried before to treat both conditions by providing the missing enzyme instead of adding genes, but it is too big to cross from the bloodstream into the brain.

By 2012, Sena-Esteves had shown that the virus and gene therapy worked in mice; Martin, at Auburn, proved the same in cats, and a third colleague, Heather Gray-Edwards, now of UMass Medical School, used it to rescue Jacob sheep.

Just before trying the approach in children, the team decided to test it in monkeys. The Food and Drug Administration probably wouldn't have required it after their success in other animals, but they wanted to be extra cautious.

The results were devastating. The monkeys became apathetic and lost dexterity, Edwards said. They clearly weren't helped.

It took years of research to figure out that the animals had gotten too much of a good thing: The extra enzymes that helped clean up the brain cells of other mammals was overwhelming and killing the monkey's cells. 

Sena-Esteves said the day he learned the results was perhaps the worst of his professional life. But it was far better to learn the lesson on monkeys. 

The therapy given to children is carefully calibrated in hopes of achieving a Goldilocks balance: not too little, but not too much. 

Lena Labdi, a research assistant at the University of Massachusetts Medical School, working in the Sena-Esteves lab on April 13, 2021 in Arlington, Mass.

Lena Labdi, a research assistant at the University of Massachusetts Medical School, working in the Sena-Esteves lab on April 13, 2021 in Arlington, Mass.
Robert Deutsch, USA TODAY

Signs of progress

Last year, Feldborg and Rokina, both now on paid leave from their sales and logistics jobs, befriended the other two Danish families whose babies had been diagnosed with Sandhoff.

One child was two months older than Alissa, the other eight months older. Neither got gene therapy. Both died earlier this year.

Doctors selected Alissa for the trial hoping she was still young enough and her losses recent enough that the damage to her brain might be reversible.

"We think that there are many cells that are simply under duress" due to the toxic build-up of fats, said Dr. Florian Eichler, a pediatric neurologist at Massachusetts General Hospital who treats Alissa. "If we can appropriately return a healthy copy of the gene and the enzyme, that cell can recover."

Last fall, watching their daughter slip further away, Feldborg and Rokina worried that Alissa would be disqualified from the trial because she had already lost too much function, or that the treatment would come too late to make a difference. 

Alissa Feldborg in physical therapy from Feldenkrais practitioner Matthew Wilkinson while dad Thomas and mom Daria watch on April 13, 2021 in Arlington, Mass.

Alissa Feldborg in physical therapy from Feldenkrais practitioner Matthew Wilkinson while dad Thomas and mom Daria watch on April 13, 2021 in Arlington, Mass.
Robert Deutsch, USA TODAY

Doctors warned them not to expect much. No one knew if the therapy would help or how long it might take to start seeing changes.

But just a week after the surgeries, Alissa's sparkling blue eyes, which had been rolling randomly and constantly, seemed to stabilize and focus. With eyes in constant motion, she couldn't have been able to see much.

Now that they're more focused, it's also easier to feel like there's someone present behind them.

In February, Alissa started to move her hands with some intention and began eating more. Swallowing was the one skill she hadn't lost, but perhaps because of the steroids that are part of her care she became hungry again, accepting spoonfuls of soft food. Recently, she learned how to suck down a bottle for the first time. 

gene therapies, for a condition called spinal muscular atrophy, showed that the treatment, while immensely effective, wasn't enough on its own. Just as newborns learn to control their limbs by moving them, so children whose brains have lost the ability to direct movement – or never developed it in the first place – need practice for the proper wiring to form.

"We say with the nervous system, you have to use it or you lose it," Eichler said. "There has to be continued stimulation, activity, and so all of those things Alissa's parents do so well with her are vital."

Waiting, wondering and hoping

People tell Feldborg how "brave" he and his wife are for trying gene therapy with Alissa. He's not sure how to respond.

"There's a fine line between bravery and stupidity," he said. "Are we so stupid in our hope? Is it a fool's mission we're on?" 

This past week, three months after her surgery, doctors began a battery of tests on Alissa to see if they can detect objective signs of progress. They're hoping to see evidence on her MRI scan that her brain is repairing itself. 

The trial would be deemed successful if it achieved any of three possible outcomes, said the NIH's Tifft: It could slow Alissa's decline, keep her from slipping any further or actually help her gain skills. 

"None of these children ever improve on their own. They just don't," Tifft said. "In a disease that only progresses downhill, even preserving function is a win."

"Then the question is, for how long," she added.

No matter what happens, the trial represents "a huge milestone" in the treatment of Sandhoff and related diseases, Eichler said.

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