Promising gene therapy delivers treatment directly to the brain

When Rylae-Ann Poulin was a year old, she didn’t crawl or babble like other children her age. A rare genetic disease did not even allow her to raise her head. Her parents took turns holding her upright at night so she could breathe and sleep comfortably.

Then, months later. doctors administered gene therapy directly into her brain.

Now the 4-year-old walks, runs, swims, reads and rides a horse – “she just does so many amazing things that doctors once thought were impossible,” said her mother, Judy Wei.

Rylae-Ann, who lives with her family in Bangkok, was one of the first people to take advantage of a new way of delivering gene therapy – targeting diseases in the brain – which experts say holds great promise for treating many brain disorders.

Her treatment recently became the first gene therapy to be delivered to the brain after being approved in Europe and the UK for AADC deficiency, a disorder that disrupts the way cells in the nervous system communicate. New Jersey drug company PTC Therapeutics plans to get US approval this year.

Meanwhile, according to the National Institutes of Health, about 30 US studies are underway testing brain gene therapy for various disorders. One, led by Dr. Krystof Bankiewicz of Ohio State University, also addresses AADC deficiency. Others are testing 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 the evidence is growing to support this approach – opening up new frontiers in the fight against disorders affecting our most complex and mysterious organ.

“There are many exciting times ahead of us,” says Bankiewicz, a neurosurgeon. “We’re seeing some breakthroughs.”


The most dramatic of these breakthroughs involves Rylae-Ann disease, which is caused by mutations in a gene needed for an enzyme that helps produce neurotransmitters like dopamine and serotonin, the body’s chemical messengers. A single treatment provides a working version of the gene.

At about 3 months old, Rylae-Ann began having spells that her parents thought were seizures – her eyes rolled back and her muscles tensed. Fluid sometimes entered her lungs after feeding, sending her to the emergency room. Doctors suspected that he might suffer from epilepsy or cerebral palsy.

Around this time, Wei’s brother sent her a Facebook post about a Taiwanese child with AADC deficiency. This extremely rare disorder affects around 135 children worldwide, many of them in this country. 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 he could qualify for a gene therapy clinical trial in Taiwan.

Although they were nervous about the prospect of brain surgery, they realized that without it, she probably wouldn’t live more than 4 years.

Rylae-Ann underwent treatment at the age of 18 months on November 13, 2019 – what her parents called “rebirth day”. Doctors delivered him in a minimally invasive operation, with a thin tube through an opening in his skull. A harmless virus carried in a functioning version of the gene.

“It gets into the brain cells, and then the brain cells produce (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 of them could finally stand and walk, Peltz said, and they got better and better over time.

Bankiewicz said that all about 40 patients in the study funded by his NIH team also saw significant improvement. His surgical approach is more involved and provides treatment for a different part of the brain. It targets the right circuits in the brain, Bankiewicz said, like planting seeds that cause ivy to sprout and spread.

“It’s really amazing work,” said Jill Morris, program director at the National Institute of Neurological Disorders and Stroke, which helped fund the research. “And he saw a lot of consistency between patients.”

One of them is 8-year-old Rian Rodriguez-Pena, who lives with her family near Toronto. Rian underwent 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 reaching for hugs. Seven months after surgery, she sat up on her own.

“With the world crashing down around us due to COVID, we celebrated at our house like it was the biggest party of our lives because Rian was just crushing so many milestones that had been impossible for so long,” said her mum, Shillann Rodriguez -Pen. “Now it’s a completely different life.”


The researchers say challenges must be overcome before this approach becomes commonplace for more common brain diseases.

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

“When you correct one gene, you know exactly where the target is,” Morris said.

Ryan Gilbert, a biomedical engineer at Rensselaer Polytechnic Institute in New York City, said there could also be problems with a gene-carrying virus that could potentially introduce genetic information in a massive manner. Gilbert and other researchers are working on other delivery methods, such as messenger RNA – a technology used in many COVID-19 vaccines – to deliver the genetic payload to the cell nucleus.

Researchers are also exploring ways to deliver gene therapy to the brain without the dangers of brain surgery. But that requires bypassing the blood-brain barrier, an inherent blockade designed to keep out viruses and other germs that may be circulating in the bloodstream outside the brain.

The more practical obstacle is cost. The cost of gene therapies, mainly borne by insurers and governments, can run into the millions. For example, a one-time PTC treatment, called Upstaza, costs over $3 million in Europe.

But drugmakers say they are committed to giving people the treatment they need. Scientists believe 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. “You’ll see more tech doing this kind of thing in the future.”

The Rylae-Ann and Rian families said they hope other families struggling with devastating genetic diseases will one day see the transformations they have seen. Both girls are still developing. Rian plays, eats different foods, learns to walk and works on his language. Rylae-Ann attends preschool, has started taking ballet lessons and reading at preschool level.

When her dad picks her up, she “runs over to me… just hugs me and says, ‘I love you, Daddy.’ he said. “It’s like it’s a normal day and that’s all we ever wanted as parents.”


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

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