A promising gene therapy delivers the treatment directly to the brain

A promising gene therapy delivers the treatment directly to the brain

A promising gene therapy delivers the treatment directly to the brain

When Rylae-Ann Poulin was one year old, she didn’t crawl or chatter like other children her age. A rare genetic disorder prevented her from even raising her head. Her parents took turns holding her up at night so she could breathe and sleep comfortably.

Then, months later. Doctors administered gene therapy directly into their brains.

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

Rylae-Ann, who lives in Bangkok with her family, was one of the first to benefit from a new type of gene therapy — fighting diseases in the brain — which experts believe shows promise for treating a variety of brain disorders .

Their treatment recently became the first brain-mediated gene therapy for AADC deficiency, a disorder that affects the way cells in the nervous system communicate, following approval in Europe and the UK. New Jersey drugmaker PTC Therapeutics plans to file for US approval this year.

According to the National Institutes of Health, there are now around 30 US studies testing brain gene therapy for various diseases. One led by Dr. Ohio State University’s Krystof Bankiewicz also targets AADC deficiency. Others are testing treatments for conditions like Alzheimer’s, Parkinson’s and Huntington’s.

Challenges remain, particularly for 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 a lot of exciting times ahead of us,” said Bankiewicz, a neurosurgeon. “We’re seeing some breakthroughs.”


The most dramatic of these breakthroughs concerns 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-off treatment delivers a working version of the gene.

At around 3 months old, Rylae-Ann started having what her parents thought were seizures – her eyes would roll back and her muscles would tighten. After eating, fluid sometimes got into her lungs, which took her to the emergency room. Doctors thought she might have epilepsy or cerebral palsy.

Around that time, Wei’s brother sent her a Facebook post about a child in Taiwan with AADC deficiency. The extremely rare disease affects about 135 children worldwide, many of them in this country. Wei, who was born in Taiwan, and her husband, Richard Poulin III, saw a doctor there who gave Rylae-Ann the correct diagnosis. They learned that she could qualify for a gene therapy clinical trial in Taiwan.

Although they were nervous about the prospect of brain surgery, they realized that without them, she probably wouldn’t live past 4 years old.

Rylae-Ann was treated on November 13, 2019 at the age of 18 months – what her parents called her “rebirth day”. Doctors put it through a hole in the skull with a thin tube during a minimally invasive operation. A harmless virus that contains a working version of the gene.

“It gets 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 their clinical trials showed motor and cognitive improvements. Some of them, Peltz said, could eventually stand and walk and get better and better over time.

Bankiewicz said all of the roughly 40 patients in his team’s NIH-funded study also saw significant improvements. Its surgical approach is more complicated and directs the 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.

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

One of them is 8-year-old Rian Rodriguez-Pena, who lives with her family near Toronto. Rian received gene therapy in 2019, just before her 5th birthday. Two months later, she held her head up for the first time. She soon started using her hands and reaching out for hugs. Seven months after the operation, she sat up on her own.

“As the world collapsed around us with COVID, we partied at our house like it was the biggest party of our lives because Rian just smashed so many milestones that were impossible for so long,” said her mother, Shillan Rodriguez-Pena . “It’s a very different life now.”


Scientists say there are still challenges to be overcome before this approach becomes widespread for more common brain disorders.

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

“When you correct 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 can also be problems with the gene-carrying virus, which can potentially insert genetic information in random ways. 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 cell’s nucleus.

Scientists are also exploring ways to deliver gene therapy to the brain without the dangers of brain surgery. But this requires bypassing the blood-brain barrier, an inherent roadblock that keeps viruses and other germs that may be circulating in the bloodstream away from the brain.

A more practical hurdle is cost. The cost of gene therapy, borne primarily by insurers and governments, can run into the millions. The unique PTC therapy called Upstaza, for example, costs more than 3 million dollars in Europe.

But drugmakers say they are committed to ensuring people get the treatments they need. And the researchers are confident they can overcome the remaining scientific barriers 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’re going to see more technology doing things like this.”

Rylae-Ann and Rian’s families said they hope other families dealing with devastating genetic diseases will one day see the changes they have seen. Both girls continue to improve. Rian plays, eats all kinds of things, learns to walk and works on the language. Rylae-Ann is in preschool, has started a ballet class, and reads at kindergarten 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 just like a normal day, and that’s all we ever wanted as parents.”


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

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