Gene Therapy May Improve Brain Tissue Integrity in AADC Deficiency, Study Suggests

Gene therapy has demonstrated the ability to improve motor function in movement disorders, including ones triggered by aromatic L-amino acid decarboxylase (AADC) deficiency, a study reports.

According to the researchers, better motor performance observed in children with AADC deficiency after undergoing gene therapy may be associated with improvements in brain tissue integrity. Starting gene therapy at an early age may lead to better brain function in these children, they also suggested.

The study, “Gene therapy improves brain white matter in aromatic L-amino acid decarboxylase deficiency,”  was published in Annals of Neurology.

AADC deficiency causes severe mental and motor delays in affected children, because the AADC enzyme is involved in the production of several brain chemical messengers, such as dopamine and serotonin. The lack of the AADC enzyme may lead to abnormal development of the brain.

In a prior Phase 1/2 clinical trial (NCT01395641), researchers at the National Taiwan University College of Medicine had shown that injecting an AADC-expressing adeno-associated viral (AAV) vector into the putamen — a brain region involved in movement control — of children with AADC deficiency improved motor development in all study subjects.

The researchers hypothesized that, after the dopamine levels are restored in the putamen, the resulting improvements in motor performance may lead to a major adaptation of brain structure.

Magnetic resonance imaging (MRI), including diffusion tensor imaging (DTI), is a noninvasive way to study the brain’s structure. Thus, the same team of scientists decided to use MRI and DTI to detect microstructural changes in the white matter of children with AADC deficiency who had undergone gene therapy. 

The brain is composed of gray and white matter. The white matter consists of nerve cell projections, known as axons or fibers, which connect distinct parts of the gray matter. The condition of the fibers influences the way the brain processes information.

The researchers analyzed MRI and DTI images of eight patients (three boys and five girls, ages 1-8 years) who underwent AADC-expressing AAV gene therapy. Images were taken from before and 12 months after gene therapy.

Data from seven of eight participants were from two separate studies, including the Phase 1/2 trial. One patient received the treatment as compassionate use. Results were compared with 15 age-matched individuals with normal MRIs used as controls.

Prior to gene therapy, white matter abnormalities were observed in the patient group, compared with the control sample. Following treatment, all patients had an increase in their white matter integrity, which was correlated with an increase in motor score, as measured by the Peabody Developmental Motor Scale-2.

The increase in white matter integrity was also inversely associated with patients’ age at the time of gene therapy, meaning younger patients had greater improvement in both motor function and white matter microstructure.

In addition, the scientists reported that some neural pathways involved in motor control had improved functioning after gene therapy.

“The current study is the first to demonstrate an improvement in white matter microstructural integrity after the correction of a movement disorder by gene therapy. Our results also suggest that gene therapy should be performed at an early age to achieve better recovery of brain function and structure,” the researchers said.