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TSuspicion that something was wrong started when the parents of the 1-year-old noticed that she was having trouble holding her head. It was just the first of what would be many missed development milestones.
At the age of 8, the little girl still couldn’t sit up on her own, hold a toy or say hello. She had trouble sleeping for more than an hour or two at a time. Several times a week her body suddenly stiffened, her eyes frozen to one side of her face, sometimes for hours. Known as an eye oculogyric crisis, it’s a tragically standard symptom of AADC deficiency, an ultra-rare genetic disorder that has deprived your brain of dopamine and serotonin, essential molecules that allow brain cells to communicate with each other.
Given her age and the nature of her condition, this girl might have seemed an unlikely candidate for experimental gene therapy. It is 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 problems. But at age 8, she became patient # 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 slipped her into an MRI machine, which they used to guide a needle deep into her brain to inject harmless viruses that carried healthy copies of the AADC gene.
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A few weeks after the operation, dopamine began to circulate between his neurons. A few months later, she started to sit up. The oculogyric seizures stopped coming and sleep thankfully did. Today Patient # 2, now 10 years old, can walk without any assistance. She also begins to speak using a speech generation device. His remarkable progress was reported in Nature Communications on Monday, along with equally compelling data from six other pediatric patients in the trial.
This was a small Phase 1 study designed purely to test safety. Yet the striking results suggest not only a viable strategy for treating a neglected and devastating disease, but a possible upheaval in what neuroscientists think they know about the brain’s ability to make new connections once freed from a genetic death sentence. .
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“It opened my eyes to see that there is no critical period in which development has to take place and if it doesn’t, that ability wears off,” Toni Pearson said, pediatric neurologist at Washington University School of Medicine. in St. Louis and a lead author of the new study. “We still believe that the sooner this could be delivered, the better the profit potential. But I think we are finding out what the plasticity window is to keep progressing.
The idea for the trial originated in 2012, shortly after Pearson met Patient # 2. At the time, Pearson was at Columbia University and had just started collaborating with a neurosurgeon from there. ‘University of California at San Francisco named Krystof Bankiewicz. Bankiewicz is now a professor of neurological surgery at Ohio State University’s Wexner Medical Center, who also treated patients as part of the trial. He had recently found a way to package the AADC gene into a harmless virus to treat patients with Parkinson’s disease. They also suffer from problems caused by a lack of dopamine, as the neurons that would normally produce the neurotransmitter gradually die off.
Dopamine only lasts a minute or two in the blood. Thus, patients with Parkinson’s disease are instead treated with its metabolic precursor, L-DOPA, which is also more easily made and can be administered orally. Once it makes its way to the brain, L-DOPA is broken down by the enzyme AADC into dopamine. The idea with Bankiewicz’s Parkinson’s gene therapy was to help the remaining neurons more efficiently convert their processing into the usable form of the neurotransmitter.
Patients with AADC deficiency have a different problem. Their neurons don’t die. They are structurally intact and produce L-DOPA very well. But then they hit a roadblock. Because their AADC gene is broken, they don’t make the enzyme that performs the last critical step to convert it to dopamine. And without it, neurons, although individually healthy, cannot communicate with each other.
Pearson and Bankiewicz believed 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 of these intact circuits. Once inside neurons, this particular virus had the gift of traveling the length of each axon, often extending into different regions of the brain, until it reached the synapse where dopamine production takes place. .
The AADC is also responsible for the final stage of serotonin production, but these neurons reside in an even harder to reach part of the brainstem. The researchers therefore decided to target only dopamine-producing cells.
They applied for funding from the National Institute of Neurological Disorders and Stroke (NINDS) and received about $ 3 million to produce the viral vector and perform the necessary toxicology studies before starting a clinical trial. They started assaying their first patients in 2017. Due to the need to use imaging to guide the delivery of gene therapy deep into the brain, they only treated patients over the age of. 4 years old, whose skulls are sufficiently formed to safely support the MRI frame required for the procedure.
According to the Nature report, seven patients between 4 and 9 were treated and none experienced adverse effects. Using a fluorescent version of L-DOPA that appears on PET scans, the researchers were able to observe that within weeks, all 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 presented with oculogyric crises. Eighteen months later, four had started to sit independently and two could walk with the help of an adult.
“This is extremely interesting data,” said Jill Morris, director of the NINDS program overseeing the trial. “This was truly a foundational study to show the benefits of gene therapy and how it can change the life of a child with a genetic disease.”
Seven months after receiving treatment, a trial participant died suddenly, which is not uncommon in patients with AADC deficiency disorder. It was determined that the death was unrelated to the gene therapy. A larger scale trial focusing on the effectiveness of gene therapy is now planned.
“The sample size is small, and while there were significant benefits for some patients, it was by no means a full recovery, possibly because they did not achieve all types of cells affected by this disease, ”said Guoping, a neuroscientist at the Massachusetts Institute of Technology. Feng, who did not participate in the study. Still, he said he found the results incredibly encouraging. Feng strongly believes that genome editing tools like CRISPR could one day reverse more complex brain disorders like autism, Huntington’s disease, schizophrenia and others. He and others have shown that it is possible to do this 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 last,” Feng said. “What we have now is one of the first evidence in humans that there is actually a fairly large postnatal window in which correcting a genetic mutation might be of benefit.”
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