Promising gene therapy delivers treatment directly to the brain

When Rylae-Ann Poulin was one year old, she didn’t crawl or chatter like other kids her age. A rare genetic defect prevented him from even raising his head. Her family took turns keeping her upright at night so she could breathe and sleep.

Then, months later. Doctors injected the gene therapy directly into his brain.

Now the 4-year-old boy walks, runs, swims, reads and rides horses. “She does so many wonderful things that doctors once said were impossible,” said her mother, Judy Wei.

Rylae-Ann, who lives with her family in Bangkok, was among the first to take advantage of the way to deliver a new gene therapy that attacks diseases within the brain, which experts believe holds great promise for treating a number of brain disorders.

His treatment became the first gene therapy given to the brain, shortly after it was approved in Europe and the UK for AADC deficiency, a disease that interferes with the way cells in the nervous system communicate. New Jersey drugmaker PTC Therapeutics plans to seek approval from the US this year.

Meanwhile, about 30 U.S. studies are underway testing gene therapy to the brain for a variety of disorders, according to the National Institutes of Health. Ohio State University’s Dr. One led by Krystof Bankiewicz also targets the lack of AADC. Others test treatments for disorders such as Alzheimer’s, Parkinson’s, and Huntington’s.

Challenges remain, especially when it comes to diseases caused by more than one gene. But scientists say there’s growing evidence to support this approach – opening a new front in the fight against disorders that affect our most complex and mysterious organ.

“We have very exciting times ahead,” said Bankiewicz, a neurosurgeon. “We’re seeing some breakthroughs.”


The most dramatic of these discoveries is Rylae-Ann disease, which is caused by mutations in a gene required for an enzyme that helps the body make neurotransmitters such as dopamine and serotonin, its chemical messengers. The one-time treatment provides a working version of the gene.

At about 3 months old, Rylae-Ann began having seizures that her parents thought were seizures – her eyes were rolling back and her muscles were tensing up. Sometimes the fluid would get into her lungs after feeding and send her to the emergency room, she said. Doctors thought it might be epilepsy or cerebral palsy.

At that time, Wei’s brother sent him a post on Facebook about a child with AADC deficiency in Taiwan. The extremely rare disease affects around 135 children worldwide, most of them in that country. Born in Taiwan, Wei and her husband, Richard Poulin III, sought out a doctor there who accurately diagnosed Rylae-Ann. They learned that he could qualify for a gene therapy clinical trial in Taiwan.

While they were nervous about the possibility of having brain surgery, they realized that he probably wouldn’t have made it past the age of 4 without him.

Rylae-Ann received treatment at the age of 18 months on November 13, 2019, which her parents called her “rebirth day.” Doctors delivered it during minimally invasive surgery with a thin tube through a hole in the skull. A harmless virus carried in a functioning version of the gene.

“It’s put into brain cells and then brain cells make the (neurotransmitter) dopamine,” said Stuart Peltz, CEO of PTC Therapeutics.

Company officials said all patients in their clinical trials showed motor and cognitive improvements. Some are eventually able to get up and walk and continue to improve over time, Peltz said.

All of the 40 or so patients in his team’s NIH-funded study also saw significant improvements, Bankiewicz said. The surgical approach is more comprehensive and delivers the treatment to a different part of the brain. Bankiewicz said it targets relevant circuits in the brain, such as planting seeds that cause ivy to sprout and spread.

“It’s really great work,” said Jill Morris, program director of the National Institute of Neurological Disorders and Stroke, which helps pay for the research. “And he saw a lot of consistency among patients.”

One is 8-year-old Rian Rodriguez-Pena, who lives with her family near Toronto. Rian received gene therapy in 2019, shortly before his 5th birthday. For the first time in two months she held her head high. Soon she began to use her hands and reach out for a hug. Seven months after the surgery she sat on her own.

“While the world was falling apart around us with COVID, we were celebrating at home like it was the biggest party of our lives because Rian was crushing so many milestones that had been impossible for so long,” said her mother, Shillann Rodriguez-Pena. “It’s a completely different life now.”


Scientists say there are challenges that must be overcome before this approach becomes mainstream for more common brain diseases.

For example, the timing of treatment is an issue. In general, early in life is better because diseases can cause a range of problems over the years. Also, disorders with more complex causes, such as Alzheimer’s, are more difficult to treat with gene therapy.

“When you fix 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 be problems with the virus carrying the gene, potentially adding genetic information in a haphazard manner. 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 nuclei of cells.

Scientists are also exploring ways to deliver gene therapy to the brain without the dangers of brain surgery. But that requires breaking through the blood-brain barrier, a natural roadblock designed to keep viruses and other microbes circulating in the bloodstream out of the brain.

A more practical hurdle is cost. Gene therapies, which are mostly covered by insurers and governments, can cost millions. For example, a one-time PTC treatment called Upstaza costs more than $3 million in Europe.

But drug makers say they’re committed to making sure people get the treatments they need. And the researchers are confident they can overcome other scientific hurdles to this approach.

“Therefore, I would say that gene therapy can be used for many brain diseases and disorders,” Gilbert said. “In the future, you’ll see more technology doing this kind of thing.”

Rylae-Ann and Rian’s families said they hope other families dealing with devastating genetic diseases will one day see the transformations they have seen. Both girls continue to improve. Rian plays, eats all kinds of food, learns to walk and works on language. Rylae-Ann is in kindergarten, she started ballet class and is studying in kindergarten.

When his father took him in his arms, he said, “She runs up to me… she just hugs me and says, ‘I love you daddy,'” she said, “as if it was a normal day and that was all we wanted as parents.”


The Associated Press Department of Health and Science has support from the Howard Hughes Medical Institute’s Science and Education Media Group. AP is solely responsible for all content.

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