A Japan-made gene therapy product has dramatically improved the lives of children and teenagers suffering from a rare neurological disorder.
Born with an inability to produce key neurotransmitters, including dopamine, those affected by aromatic L-amino acid decarboxylase (AADC) deficiency begin to show signs of mobility and cognitive delays in early infancy. Many patients are non-verbal. Most become bedridden for life.
By engineering a virus to deliver a working copy of the mutated gene responsible for the disease, clinicians at Jichi Medical University in Tochigi have now shown that they can improve the motor functions of severely disabled patients and, in some cases, even enhance cognitive and language abilities.
The Jichi team — led by pediatric neurologist Takanori Yamagata — used an adeno-associated virus (AAV) as a delivery vehicle for DNA encoding the recipe for making a functional AADC enzyme. The researchers administered the one-time gene therapy treatment to six patients aged four to 19 years. Each patient received approximately 200 billion copies of the AAV injected directly into two parts of the putamen, a round structure located at the base of the forebrain that is involved in learning and motor control.
Within months of the treatment, all six patients could control their heads and sit with support. Three patients with more severe symptoms could also stand with something to lean on; one person even managed to take steps using a walker.
Muscle tone remained poor, but all patients showed improvements in swallowing and breathing, and one girl who had required a nasogastric tube was weaned off it and could eat orally. Some patients were able to make sounds that resembled words. All seemed to understand language better.
One young girl with a more moderate form of the disease showed the most striking response to the therapy. Before the trial, she was somewhat ambulatory but could only walk with help. After receiving the gene therapy, she could run, ride a bicycle, play on a swing all by herself and converse fluently with others. Besides a little floppiness in her muscles, she “looked like a healthy young girl,” the authors report in the journal Brain.
Researchers in Taiwan have evaluated a similar gene therapy product in 26 children with AADC deficiency, and also documented clinically meaningful and sustained improvements in motor, cognitive and language milestones. But that patient population tended to be younger and more genetically homogenous than the Japanese cohort.
The Jichi study thus offers independent validation for the treatment strategy and suggests it can still be effective in older patients, including those with variable root causes and manifestations of the disease.
The program-affiliated researchers contributing to this research are from Jichi Medical University, Japan.
- Kojima, K., Nakajima, T., Taga, N., Miyauchi, A., Kato, M. et al. Gene therapy improves motor and mental function of aromatic l-amino acid decarboxylase deficiency. Brain 142, 322–333 (2019). | Article