Promising gene therapy delivers treatment directly to the brain

Promising gene therapy delivers treatment directly to the brain

When Rylae-Ann Poulin was one year old, she didn’t crawl or babble like other kids her age. Due to a rare genetic condition, she couldn’t even lift her head. Her parents took turns holding her upright so she could breathe and sleep comfortably.

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

Now the 4-year-old is walking, running, swimming, reading and riding horses — “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 take advantage of a new way to deliver gene therapy – attacking diseases in the brain – that experts say holds great promise for the treatment of a host of diseases. brain disorders.

Her treatment recently became the first brain-delivered gene therapy after approval in Europe and the UK for AADC deficiency, a condition that interferes with the way cells in the nervous system communicate. New Jersey-based drugmaker PTC Therapeutics plans to seek U.S. approval this year.

Meanwhile, according to the National Institutes of Health, about 30 U.S. studies are underway testing gene therapy on the brain for various conditions. One, led by Dr. Krystof Bankiewicz at Ohio State University, also focuses on AADC deficiency. Others are testing treatments for conditions such as Alzheimer’s, Parkinson’s and Huntington’s.

Challenges remain, especially in diseases caused by more than one single gene. But scientists say the evidence supporting this approach is mounting – opening a new frontier in the fight against conditions that affect our most complex and mysterious organ.

“We have a lot of exciting times ahead of us,” says Bankiewicz, a neurosurgeon. “We’re seeing some breakthroughs.”


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

When she was about 3 months old, Rylae-Ann started having spells that her parents thought were seizures – her eyes rolled back and her muscles tensed. Fluid sometimes entered her lungs after feedings, sending her to the emergency room. Doctors thought she might have epilepsy or cerebral palsy.

Around that time, Wei’s brother sent her a Facebook message about a child in Taiwan with an AADC deficiency. The extremely rare condition affects about 135 children worldwide, many in that country. A native of Taiwan, Wei and her husband, Richard Poulin III, sought a doctor there who correctly diagnosed Rylae-Ann. They found out that she could qualify for a gene therapy clinical trial in Taiwan.

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

Rylae-Ann underwent the treatment when she was 18 months old on November 13, 2019 – what her parents have dubbed her ‘born again day’. Doctors delivered it during minimally invasive surgery, with a thin tube passed through a hole in the skull. A harmless virus in a functioning 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, were eventually able to stand and walk and get better and better over time.

Bankiewicz said all of the approximately 40 patients in his team’s NIH-funded study also saw significant improvements. His surgical approach is more involved and takes the treatment to a different part of the brain. It targets relevant circuits in the brain, Bankiewicz said, such as planting seeds that cause ivy to sprout and spread.

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

One is 8-year-old Rian Rodriguez-Pena, who lives with her family near Toronto. Rian received gene therapy in 2019, shortly before her 5th birthday. Two months later, she held her head up for the first time. Soon she started using her hands and reaching for hugs. Seven months after surgery, she sat up.

“When the world came crashing down around us with COVID, we celebrated 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, Shillann Rodriguez-Pena. . “It’s a whole different life now.”


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

For example, the timing of treatment is a problem. In general, early in life is better, as illnesses can cause an accumulation of problems over the years. Disorders with more complex causes, such as Alzheimer’s disease, are also more difficult to treat with gene therapy.

“If 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, said there could also be problems with the gene-carrying virus, which may be able to insert genetic information in a random way. 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 bypassing the blood-brain barrier, an inherent roadblock designed to keep viruses and other germs that might be circulating in the bloodstream out of the brain.

A more practical hurdle is cost. The price of gene therapies, largely borne by insurers and governments, can run into the millions. For example, the one-time PTC therapy, called Upstaza, costs more than $3 million in Europe.

But drugmakers say they are committed to making sure people get the treatments they need. And researchers are confident they can overcome the remaining scientific obstacles to this approach.

“So I would say gene therapy can be used for many types of brain diseases and disorders,” Gilbert said. “In the future you will 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’ve seen. Both girls continue to improve. Rian is playing, eating all kinds of things, learning to walk and working on language. Rylae-Ann is in kindergarten, has started ballet class and is reading at kindergarten level.

When her dad picks her up, she “runs over to me… just gives me a hug 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 division is supported by the Science and Educational Media Group of the Howard Hughes Medical Institute. The AP is solely responsible for all content.

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