AADC Activity in Brain Evident 2 Years After Gene Therapy, Trial Data Show

A viral vector-delivered gene therapy can restore the activity of the AADC enzyme in people with AADC deficiency for at least two years, research drawing on clinical trial data shows.

Findings were in the study “Dopaminergic restoration of prefrontal cortico-putaminal network in gene therapy for aromatic L-amino acid decarboxylase deficiency,” published in Brain Communications.

AADC is caused by mutations in the gene DDC. These mutations render the body unable to make the AADC (aromatic L-amino acid decarboxylase) enzyme, which is needed to make certain neurotransmitters (brain signaling molecules) such as dopamine.

Gene therapy is currently under investigation as a potential therapeutic approach for AADC deficiency. This therapy aims to deliver a non-mutated version of the DDC gene to a patient’s cells, thus allowing them to make a functional AADC enzyme.

Researchers in Japan assessed a gene therapy’s effects on AADC enzyme activity in patients’ brains, using data from an open-label Phase 1/2 trial (UMIN000017802) in that country that tested a gene therapy called AAV2-hAADC in eight young patients.  Previously published trial results indicated the therapy was well-tolerated and led to improved motor and cognitive skills.

Enrolled patients ranged in age from 4 to 19; five were male, and three were female. Five were Japanese Asian, two were non-Japanese Asian, and one was Caucasian.

The gene therapy was administered to all during a surgery, and it was injected into a specific part of the brain called the putamen, which is enriched with dopamine.

To assess AADC activity in patients’ brains, the researchers used a technique called FMT-PET. This technique uses a specialized tracer called FMT (6-[18F]fluoro-L-m-tyrosine) that is taken up by active AADC. The tracer can be visualized by a PET scan, allowing researchers to indirectly measure AADC activity.

This work demonstrated that AADC activity in the putamen of these patients increased substantially within six months of the gene therapy being administered. AADC activity in the putamen also remained high at two years post-therapy, the latest time point assessed. Of note, other parts of the brain — areas where the therapy was not injected — generally showed little or no AADC activity.

Further analyses showed increased connectivity between the putamen and other brain regions — including, notably, many regions known to be important in controlling movement, like the prefrontal cortex.

Broadly, these findings indicated that AAV2-hAAD worked as expected: that is, they suggest that the gene therapy could restore AADC activity, leading to more normalized brain activity and easing motor symptoms.

“We found that motor improvement is associated with dopaminergic restoration of the putaminal area that belongs to the prefrontal cortico-putaminal network … which contributes to cognitive-motor control function, including motor initiation and planning,” the researchers wrote.

“The results suggest that putaminal dopamine promotes the development of an immature motor control system, particularly in the human prefrontal cortex that is primarily affected by AADC deficiency,” the team concluded.