A Gene-replacement therapy that is administered directly to the brain has allowed some children with a rare genetic condition to walk and talk for the first time.
“It’s a dream come true,” says Richard Poulin, whose daughter Rylae-Ann received the therapy in November 2019, aged 18 months. Rylae-Ann, who lives in Thailand, went from being unable to say any words, move or even lift her head to “running, jumping, kicking a ball, riding a horse, swimming and speaking in multiple languages”, according to Poulin.
Rylae-Ann was born with AADC deficiency, a genetic condition with fewer than 150 documented cases worldwide. It is caused by a faulty variant of a gene called DDC that prevents the brain from making dopamine and serotonin.
Without these important neurotransmitters, children with AADC deficiency “don’t have head control, they cannot sit up, they cannot walk or talk – they are bedridden”, says Wuh-Liang Hwu at the National Taiwan University Hospital, who led a clinical trial of the gene therapy, called Upstaza.
Many also experience “oculogyric crises”, where their eyes roll up into their heads. Most die at a young age, he says.
Upstaza was developed by PTC Therapeutics, a pharmaceutical company based in New Jersey. It replaces the faulty DDC gene with a version that functions normally. This version is delivered into brain cells via a virus called adeno-associated virus type 2, modified so it doesn’t harm.
The treatment is infused into a part of the brain called the putamen through a small hole that is drilled into the skull.
Since 2010, Hwu and his colleagues have trialled the gene therapy in 30 children with AADC deficiency at the National Taiwan University Hospital. The children ranged from 18 months to 10 years old at the time of treatment and mostly lived in Taiwan and other South-East Asian countries, where the condition is most prevalent.
Following treatment, the children all improved in their motor and cognitive function, and had fewer oculogyric crises, according to clinical trial results presented at the annual symposium of the Society for the Study of Inborn Errors of Metabolism in Freiburg, Germany.
“The ones who got it before 4 years of age, it’s quite a dramatic difference,” says Hwu. “We say they have been reborn.”
Rylae-Ann sat up just one month after receiving the gene therapy. She is one of seven trial at about 30 percent the speed of light. The researchers were only able to see it for two orbits before it faded from view, meaning it was either destroyed or was no longer emitting light in wavelengths ALMA can observe.
“The bubble cannot be too small, because a small bubble would not disappear that quickly,” says Wielgus. A small bubble would participants who have since learned to walk and one of three who have learned to talk. “Speech is the most difficult thing for patients to learn because it uses so many muscles,” says Hwu.
A common side effect of the gene therapy was dyskinesia, or sudden, uncontrolled movements, but this resolved in all cases.
In the past, some early gene therapies caused cancer. Upstaza shouldn’t stimulate abnormal cell growth because the virus used to deliver the DDC gene variant is non-replicating, as are the brain cells it is delivered to, says Hwu.
The gene therapy was approved by the European Medicines Agency in July. PTC Therapeutics plans to seek approval from the US Food and Drug Administration.
Poulin says the therapy has worked better for Rylae-Ann, now 4, than he and her mother Judy could have ever hoped. “We didn’t know what to expect – would she be able to lift her head? But now, when I get home, she runs up and gives me a big hug and kiss and says, ‘Daddy, Daddy, I love you’,” he says. “It’s incredible.”
