The Washington Post
New gene therapy approaches show ‘breakthroughs’ against rare condition
When Rylae-ann Poulin was a year old, she didn’t crawl or babble like other children 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 brain.
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 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 aromatic l-amino acid decarboxylase (AADC) deficiency, a disorder that interferes with the way cells in the nervous system communicate. U.S. 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 neurosurgeon 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 organ.
“There’s a lot of exciting times ahead of us,” Bankiewicz said. “We’re seeing some breakthroughs.”
The most dramatic 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 gene.
At about 3 months old, RylaeAnn 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 palsy.
Around that time, Wei’s brother sent her a Facebook post about a child in Taiwan with AADC deficiency. The 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 diagnosed Rylae-ann. They learned she could qualify for a gene therapy clinical trial in Taiwan.
Rylae-ann had the treatment at 18 months old on Nov. 13, 2019. 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.
PTC Therapeutics 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.
Scientists say there are challenges to overcome.
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 — such as Alzheimer’s — are tougher to treat with gene therapy.
Ryan Gilbert, a biomedical engineer at New York’s Rensselaer Polytechnic Institute, said there can also be issues with the genecarrying 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 vaccines for the coronavirus — 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 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 of dollars. 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.”