Gene therapy success offers hope for reversing rare genetic diseases
A landmark study published in the journal Nature Communications is describing the extraordinarily successful results of a Phase 1 trial testing a targeted gene therapy for children with a rare genetic disease. The research demonstrates a novel method for delivering gene therapies to specific locations deep in the brain and suggests these kinds of genetic treatments could reverse damage in older subjects born with developmental diseases.
The research focused on children born with a very rare genetic disorder called AADC deficiency. The condition involves a single gene mutation that leads to a deficiency in synthesizing key neurotransmitters – dopamine and serotonin. Children born with the disease suffer severe developmental deficits and motor disabilities, often leaving them unable to speak or feed themselves.
The new trial spun off from previous work looking at AADC gene therapy in patients with Parkinson’s disease. While Parkinson’s disease is also characterized by dopamine problems, AADC deficiency is specifically due to a mutated AADC gene.
Krystof Bankiewicz, a senior author on the new study, pioneered a gene therapy to treat Parkinson’s patients with a healthy AADC gene. Trials testing that therapy are ongoing but he and other scientists wondered whether the treatment would work for children with AADC deficiency.
“The approach for treating AADC deficiency is much more straightforward than it is for Parkinson’s,” explains Bankiewicz. “In AADC deficiency, the wiring of the brain is normal, it’s just the neurons don’t know how to produce dopamine because they lack AADC.”
This was not the first time gene therapy had been tested for children with AADC deficiency. Trials recently completed in Taiwan and Japan demonstrated some clinical benefits but they were incredibly minor.
Those prior trials followed the same methods of AADC gene therapy developed for Parkinson’s disease, which involved direct infusion into a part of the brain called the putamen. But Bankiewicz and colleagues wondered if the gene therapy would be more effective in children with this condition if it were delivered to a different brain region.
The researchers focused on two specific regions in the midbrain: the substantia nigra pars compacta and the ventral tegmental area, both of which are high in dopamine-producing neurons.
To deliver the gene therapy to these specific brain regions the researchers utilized a new surgical technique involving real-time magnetic resonance imaging. James Elder, a neurosurgeon working on the project, says the procedure allows the surgeons to watch the treatment spread through the brain as it is slowly infused.
"Really, what we're doing is introducing a different code to the cell," says Elder. ”And we're watching the whole thing happen live. So we continuously repeat the MRI and we can see the infusion blossom within the desired nucleus."
Seven children aged between four and nine were recruited for this Phase 1 trial. Within months of the gene therapy procedure six of the children no longer experienced seizures common to the disease.
“Remarkably, these episodes were the first to disappear and they never returned,” says Bankiewicz. “In the months that followed, many patients experienced life-changing improvements. Not only did they begin laughing and have improved mood, but some were able to start speaking and even walking.”
No adverse effects were linked with the gene therapy treatment. One subject did die seven months after the treatment, however, the researchers note the cause of death was most likely linked to the AADC deficiency disease rather than the gene therapy.
AADC deficiency is a very rare genetic disorder, with not many more than 100 children around the world currently affected. But the implications of this novel study are broader than merely a novel treatment for this rare genetic disorder.
As well as demonstrating a new surgical method for delivering gene therapy to specific brain regions, the trial shows gene therapy can still be effective when delivered several years after birth. Before this study it was unclear whether correcting a heritable genetic defect so long after birth would be effective. Some researchers suspected the developmental damage could be irreversible but these findings suggest we may have a larger window of plasticity in which to correct genetic errors.
“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,” says lead author Toni Pearson in an interview with StatNews. “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 new research was published in the journal Nature Communications.