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The suspicion that something was wrong started when the 1-year-old girl’s parents noticed she had trouble holding up her head. It was just the first of what would be many missed developmental milestones.

By the time she was 8, the little girl still couldn’t sit up on her own, hold a toy, or say hello. She had trouble sleeping more than an hour or two at a time. Several times each week, her body would suddenly stiffen, her eyes frozen to one side of her face, sometimes for hours. Known as an oculogyric crisis, it is a tragically standard symptom of AADC deficiency, an ultra-rare genetic disorder that starved her brain of dopamine and serotonin, essential molecules that allow brain cells to communicate with one another.

Given her age and the nature of her condition, this girl might have seemed an unlikely candidate to receive an experimental gene therapy. It’s a matter of vigorous scientific debate whether correcting a genetic error that causes a developmental disease like hers, so long after birth, can actually reverse some of the brain’s wiring glitches. But at 8 years old, she became Patient No. 2 in a landmark clinical trial that suggests it’s not too late for gene therapy to help such children. Doctors at the University of California, San Francisco, slid her into an MRI machine, which they used to guide a needle deep into her brain to inject harmless viruses carrying healthy copies of the AADC gene.


A few weeks after the surgery, dopamine started flowing between her neurons. A few months after that, she began to sit up. The oculogyric crises stopped coming and sleep, mercifully, did. Today, Patient No. 2, now 10 years old, can walk without any help. She’s also starting to talk using a speech-generating device. Her remarkable progress was reported Monday in Nature Communications, along with similarly compelling data from six other pediatric patients in the trial.

It was a small Phase 1 study designed only to test safety. Yet the striking results suggest not only a viable strategy to treat a neglected and devastating disease, but a possible upheaval of what neuroscientists think they know about the brain’s ability to make new connections once freed from a genetic death sentence.


“It’s been eye-opening for me to see that there’s not a critical period of time at which development has to take place and if it doesn’t, that capacity vanishes,” said Toni Pearson, a pediatric neurologist at Washington University School of Medicine in St. Louis and a lead author of the new study. “We still think that the earlier this could be delivered, the better the potential for benefit. But I think we’re discovering what the window of plasticity is for still making progress.”

The idea for the trial was born back in 2012, not long after Pearson met Patient No. 2. Back then, Pearson was at Columbia University and had just started to collaborate with a University of California, San Francisco neurosurgeon named Krystof Bankiewicz. Bankiewicz is now a neurological surgery professor at The Ohio State University Wexner Medical Center, which also treated patients in the trial. He had recently figured out a way to package the AADC gene inside a harmless virus to treat patients with Parkinson’s disease. They also suffer from problems caused by a lack of dopamine, because the neurons that would normally produce the neurotransmitter progressively die off.

Dopamine only lasts a minute or two in the bloodstream. So Parkinson’s patients are instead treated with its metabolic precursor, L-DOPA, which is also more easily manufactured and can be given orally. Once it travels to the brain, L-DOPA is broken down by the AADC enzyme into dopamine. The idea with Bankiewicz’s Parkinson’s gene therapy was to help the remaining neurons more efficiently convert their treatment into the usable form of the neurotransmitter.

Patients with AADC deficiency have a different problem. Their neurons aren’t dying. They’re structurally intact and churning out L-DOPA just fine. But then they hit a roadblock. Because their AADC gene is broken, they don’t make the enzyme that performs the critical last step to convert it to dopamine. And without it, the neurons, though individually healthy, can’t communicate with each other.

Pearson and Bankiewicz thought that if they could deliver a healthy copy of the AADC gene to the part of the midbrain where dopamine-producing neurons congregate, they could take advantage of all that intact circuitry. Once inside neurons, this particular virus had a knack for traveling along the length of each axon, often stretching into different brain regions, until it reached the synapse where dopamine production takes place.

AADC is also responsible for the final step in serotonin production, but these neurons reside in an even harder-to-reach part of the brainstem. So the researchers decided to only target the dopamine-producing cells.

They applied for funding from the National Institute of Neurological Disorders and Stroke (NINDS), and were awarded around $3 million to produce the viral vector and perform the toxicology studies required before starting a clinical trial. They began dosing their first patients in 2017. Because of the need to use imaging to guide the gene-therapy delivery deep into the brain, they only took on patients older than 4, whose skulls formed enough to safely withstand the MRI headframe required for the procedure.

According to the Nature report, seven patients between 4 and 9 were treated and none experienced any adverse effects. Using a fluorescent version of L-DOPA that shows up on PET scans, the researchers were able to observe that within a few weeks, all of the patients had recovered the ability to convert it to dopamine. As expected, the gene therapy did not alter any of the patients’ serotonin levels.

Three months after surgery, six of the seven patients no longer experienced oculogyric crises. Eighteen months later, four had began to sit independently and two could walk with the aid of an adult.

“It’s extremely exciting data,” said Jill Morris, a NINDS program director who is overseeing the trial. “It really has been a seminal study in showing the benefits of gene therapy and how it can change the life of a child that has a genetic disorder.”

Seven months after receiving treatment, one trial participant died suddenly, which is not uncommon in patients with AADC deficiency disorder. The death was determined to be unrelated to the gene therapy. A larger trial focused on the efficacy of gene therapy is now being planned.

“The sample size is small, and though there was significant benefit to some patients, it was by no means a total recovery, probably because they did not get into all the cell types impacted by this disease,” said Massachusetts Institute of Technology neuroscientist Guoping Feng, who was not involved in the study. Still, he said he found the results incredibly encouraging. Feng is a firm believer that genome editing tools like CRISPR might one day reverse more complicated brain disorders like autism, Huntington’s disease, schizophrenia, and others. He and others have shown it’s possible to do so in mice and other animal models, but so far not in humans.

“The field needs these kinds of translational experiments because humans are different, and it’s hard to predict how the results will hold up,” said Feng. “What we have now is some of the earliest evidence in humans that there is actually quite a big postnatal window in which correcting a genetic mutation might be beneficial.”

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