BREAKTHROUGH TREATMENT. Rylae-Ann Poulin attends physical education
class at Ruamrudee International School in Bangkok, Thailand, on January
13, 2023. The extremely rare AADC deficiency disorder afflicts about 135
children worldwide, many in Taiwan. Judy Wei, who was born in Taiwan,
and her husband Richard Poulin III, sought out a doctor there who
correctly diagnosed Rylae-Ann. They also learned she could qualify for a
gene therapy clinical trial in Taiwan. Rylae-Ann received the treatment
on November 13, 2019. (AP Photo/Sakchai Lalit)
From The Asian Reporter, V33, #2 (February 6, 2023), pages 10
Promising gene therapy delivers treatment directly
By Laura Ungar
The Associated Press
When Rylae-Ann Poulin was a year old, she didn’t crawl or babble like
other kids her age. A rare genetic disorder kept her from even lifting
her head. Her parents took turns holding her upright at night just so
she could breathe comfortably and sleep.
Then, months later. doctors delivered gene therapy directly to her
Now the 4-year-old is walking, running, swimming, reading, and riding
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 among the first
to benefit from a new way of delivering gene therapy — attacking
diseases inside the brain — that experts believe holds great promise for
treating a host of brain disorders.
Her treatment recently became the first brain-delivered gene therapy
after its approval in Europe and the United Kingdom for AADC deficiency,
a disorder that interferes with the way cells in the nervous system
communicate. New Jersey drugmaker PTC Therapeutics plans to seek U.S.
approval this year.
Meanwhile, about 30 U.S. studies testing gene therapy to the brain
for various disorders are ongoing, according to the National Institutes
of Health. One, led by Dr. Krystof Bankiewicz at Ohio State University,
also targets AADC deficiency. Others test treatments for disorders such
as 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
afflicting our most complex and mysterious organ.
"There’s a lot of exciting times ahead of us," said Bankiewicz, a
neurosurgeon. "We’re seeing some breakthroughs."
The most dramatic of those breakthroughs involve Rylae-Ann’s 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
At around 3 months old, Rylae-Ann began having spells her parents
thought were seizures — her eyes would roll back and her muscles would
tense. Fluid sometimes got into her lungs after feedings, sending her to
the emergency room. Doctors thought she might have epilepsy or cerebral
Around that time, Wei’s brother sent her a Facebook post about a
child in Taiwan with AADC deficiency. The extremely rare disorder
afflicts about 135 children worldwide, many in that 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 she could
qualify for a gene therapy clinical trial in Taiwan.
Though they were nervous about the prospect of brain surgery, they
realized she likely wouldn’t live past 4 years old without it.
Rylae-Ann had the treatment at 18 months old on November 13, 2019 —
which her parents have dubbed her "reborn 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
"It gets put into the brain cells and then the brain cells make the
(neurotransmitter) dopamine," said Stuart Peltz, CEO of PTC
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 continue getting better over time.
Bankiewicz said all 40 or so patients in his team’s NIH-funded study
also saw significant improvements. His surgical approach is more
involved and delivers 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 with
the National Institute of Neurological Disorders and Stroke, which
helped pay for the research. "And he has seen a lot of consistency
One is 8-year-old Rian Rodriguez-Pena, who lives with her family near
Toronto. Rian got gene therapy in 2019, shortly before her 5th birthday.
Two months later, she held her head up for the first time. She soon
started using her hands and reaching for hugs. Seven months after
surgery, she sat up on her own.
"When the world was crumbling around us with COVID, we were at our
house celebrating like it was the biggest party of our lives because
Rian was just crushing so many milestones that were impossible for so
long," said her mom, Shillann Rodriguez-Pena. "It’s a completely
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 an issue. Generally, earlier
in life is better because diseases can cause a cascade of problems over
the years. Also, disorders with more complex causes — like Alzheimer’s —
are tougher to treat with gene therapy.
"When you’re correcting one gene, you know exactly where the target
is," said Morris.
Ryan Gilbert, a biomedical engineer at New York’s Rensselaer
Polytechnic Institute, said there can also be issues with the
gene-carrying virus, which can potentially insert genetic information in
an indiscriminate 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
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 roadblock 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
mostly by insurers and governments, can run into the millions. The
one-time PTC therapy, called Upstaza, costs more than $3 million in
Europe, for example.
But drugmakers say they are committed to ensuring 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 leveraged for many sorts of brain
diseases and disorders," Gilbert said. "In the future, you’re going to
see more technology doing these kinds of things."
The families of Rylae-Ann and Rian said they hope other families
dealing with devastating genetic diseases will someday get to see the
transformations they’ve seen. Both girls are continuing to improve. Rian
is playing, eating all sorts of foods, learning to walk, and working on
language. Rylae-Ann is in preschool, has started a ballet class, and is
reading at a kindergarten level.
When her dad picks her up, "she runs 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 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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