When Rylae-Ann Poulin was one year old, she didn’t crawl or babble like other children her age. A rare genetic disorder prevented him from even raising his head. Her parents took turns holding her up at night so she could breathe comfortably and sleep.
Then months later. doctors administered gene therapy directly into his brain.
Now the 4-year-old walks, runs, swims, reads and rides horses, “just doing so many amazing things that doctors once said were impossible,” said her mother, Judy Wei.
Rylae-Ann, who lives with her family in Bangkok, was one of the first to benefit from a new way of delivering gene therapy (attacking diseases within the brain) that experts say holds great promise for treating a host of disorders. cerebral.
His treatment recently became the first gene therapy delivered to the brain after its approval in Europe and the UK for AADC deficiency, a disorder that interferes with the way cells in the nervous system communicate. New Jersey drugmaker PTC Therapeutics plans to seek US approval this year.
Meanwhile, about 30 US studies testing gene therapy in the brain for various disorders are underway, according to the National Institutes of Health. One, led by Dr. Krystof Bankiewicz of The Ohio State University, also focuses on AADC deficiency. Others are testing treatments for disorders like Alzheimer’s, Parkinson’s, and Huntington’s.
Challenges remain, especially with diseases caused by more than a single gene. But scientists say the evidence supporting this approach is mounting, opening a new frontier in the fight against disorders affecting our most complex and mysterious organ.
“We have many exciting times ahead of us,” said Bankiewicz, a neurosurgeon. “We are seeing some progress.”
The most dramatic of those advances involves Rylae-Ann disease, which is caused by mutations in a gene needed for an enzyme that helps make neurotransmitters like dopamine and serotonin, the body’s chemical messengers. The one-time treatment delivers a working version of the gene.
At around 3 months of age, Rylae-Ann began having episodes that her parents thought were seizures: her eyes would roll back and her muscles would tense up. She would sometimes get fluid in her lungs after taking hers and send her to the emergency room. The doctors thought that she might have epilepsy or cerebral palsy.
Around this time, Wei’s brother sent him a Facebook post about a boy in Taiwan with AADC deficiency. The extremely rare disorder affects an estimated 135 children worldwide, many in the United States. Wei, who was born in Taiwan, and her husband, Richard Poulin III, sought out a doctor there who correctly diagnosed Rylae-Ann. They learned that she could qualify for a gene therapy clinical trial in Taiwan.
Although they were nervous about the possibility of brain surgery, they realized that he probably wouldn’t live more than 4 years without it.
Rylae-Ann received the treatment at 18 months on November 13, 2019, which her parents called her “rebirth day.” Doctors administered it during minimally invasive surgery, with a thin tube through a hole in the skull. A harmless virus carried on a functional version of the gene.
“It’s put into the brain cells and then the brain cells make the (neurotransmitter) dopamine,” said Stuart Peltz, CEO of PTC Therapeutics.
Company officials said all patients in its clinical trials showed motor and cognitive improvements. Some of them, Peltz said, would eventually be able to stand up and walk, and continue to improve over time.
Bankiewicz said all 40 or more patients in his team’s NIH-funded study also saw significant improvements. His surgical approach is more complicated and takes treatment to a different part of the brain. It targets relevant circuits in the brain, Bankiewicz said, like planting seeds that cause ivy to sprout and spread.
“This is really amazing work,” said Jill Morris, program director at the National Institute of Neurological Disorders and Stroke, which helped pay for the research. “And you’ve seen a lot of consistency among patients.”
One is Rian Rodríguez-Pena, 8, who lives with his family near Toronto. Rian received gene therapy in 2019, shortly before her 5th birthday. Two months later, she raised her head for the first time. She soon began using her hands and seeking hugs. Seven months after surgery, she sat up on her own.
“When the world was crashing around us with COVID, we were at home celebrating like it was the biggest party of our lives because Rian was passing so many milestones that were impossible for so long,” said her mother, Shillann Rodríguez-Pena. . “It’s a completely different life now.”
The scientists say there are challenges to overcome before this approach becomes widespread for the most common brain diseases.
For example, the timing of treatment is an issue. In general, earlier in life is better because illnesses can cause a cascade of problems over the years. Furthermore, disorders with more complex causes, such as Alzheimer’s, are more difficult to treat with gene therapy.
“When you’re correcting a gene, you know exactly where the target is,” Morris said.
Ryan Gilbert, a biomedical engineer at Rensselaer Polytechnic Institute in New York, said there may also be problems with the gene-carrying virus, which can potentially insert genetic information indiscriminately. Gilbert and other researchers are working on other delivery methods, such as messenger RNA, the technology used in many COVID-19 vaccines, to deliver a genetic payload to the nucleus of cells.
Scientists are also exploring ways to deliver gene therapy to the brain without the dangers of brain surgery. But that requires getting around the blood-brain barrier, an inherent obstacle designed to keep viruses and other germs that may be circulating in the bloodstream out of the brain.
A more practical hurdle is cost. The price of gene therapies, borne mainly by insurers and governments, can run into the millions. PTC’s unique therapy, called Upstaza, costs more than $3 million in Europe, for example.
But drugmakers say they are committed to making sure people get the treatments they need. And the researchers are confident they can overcome the remaining scientific hurdles to this approach.
“So I would say that gene therapy can be used for many types of brain diseases and disorders,” Gilbert said. “In the future, you’ll see more technology doing these kinds of things.”
The families of Rylae-Ann and Rian said they hope that other families dealing with devastating genetic diseases will one day see the transformations they have seen. Both girls continue to improve. Rian is playing, eating all kinds of food, learning to walk and working on language. Rylae-Ann is in preschool, has started a ballet class, and is reading at the kindergarten level.
When her dad picks her up, “she runs up to me…she just gives me a hug and says, ‘I love you, dad.’ he said. “It’s like it’s a normal day, and that’s all we ever wanted as parents.”
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