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Gene therapy success in trial to treat neurodegenerative disorder

19 July 2021
Appeared in BioNews 1104

An innovative gene therapy directed to the brain has improved the motor function and general wellbeing of children with a rare genetic disorder.

Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare genetic brain disorder, resulting in the patient being unable to eat, talk, or walk on their own. Scientists developed a method to deliver a healthy copy of the AADC gene to specific areas of the brain so that cells would make a missing enzyme. After the procedure, all children that participated in the clinical trial showed a decrease in symptoms and an improvement in motor function.

'In the months that followed [the start of the gene therapy], 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' said corresponding author of the study Professor Krystof Bankiewicz, from the University of California San Francisco, California.

Patients with AADC deficiency have functional neuronal pathways, but lack the enzyme involved in the synthesis of neurotransmitters, particularly dopamine, which is an essential molecule that allows brain cells to communicate. Surgeons used magnetic resonance imaging to guide a needle in real time that delivers a harmless virus carrying healthy copies of the AADC gene deep into the midbrain.

The results published in Nature Communications showed all of the seven patients (aged four to nine) had recovered the ability to produce dopamine, resulting in improved motor function, including greater head control and better limb movements. After three months, six patients treated no longer had oculogyric crisis episodes, a symptom of AADC deficiency involving an involuntary upward fixed gaze that may last for hours and may be accompanied by seizures. At 12 months, four could sit independently, two could walk with help and one could speak with a vocabulary of about 50 words. One child was able to walk without support after 2.5 years.

Previously, it was not believed that a genetic error that causes a developmental disease could be corrected so long after birth. This study suggests that the brain does have the ability to make new neural connections once the genetic error has been corrected.

'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,' Dr Toni Pearson, a paediatric neurologist at Washington University School of Medicine in St. Louis, Missouri and co-first author of the study told STAT News. '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.'

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