Gene Therapy for AADC Deficiency Given Boost by NIH Grant

The development of new gene therapy to treat people with aromatic L-amino acid decarboxylase (AADC) deficiency has been boosted by an R21 grant awarded by the National Institutes of Health National Advisory Neurological Disorders and Stroke Council.

The award was given to a team of researchers at the Ohio State University College of Medicine under the direction of professor Krystof Bankiewicz, MD, PhD. He will use animal models to determine the best way to deliver the gene therapy directly to the nerve cells (neurons) in areas of the brain most affected by the condition. 

“In our view, the proposed research will have a significant impact on public health,” Bankiewicz said in a press release. “Although AADC deficiency is a rare pediatric disease, the burden to caregivers, and the cost to society is large over the life of the patients — not to mention the plight of the patients themselves. In the larger sense, projects like this will continue to enhance our ability to treat inherited neurological diseases,” he said.

AADC deficiency is caused by mutations in the DDC gene, which provides instructions to make the AADC enzyme. 

This enzyme is vital for the production of two essential neurotransmitters (molecules that mediate the communication between neurons): dopamine and serotonin. People with AADC deficiency have lower levels of these neurotransmitters, which impedes communication between the brain and other organs.

A gene therapy approach (AAV2-hAADC) initially developed for people with Parkinson’s disease, involves delivering a functional copy of the DDC gene to the cells most affected using a harmless adeno-associated virus type 2 (AAV2).

Initial studies reported success in delivering the DDC gene to the correct areas of the brain in Parkinson’s patients, who also have a shortage of dopamine.

Recently, a Phase 1 clinical study in Taiwan, in which AAV2-hAADC was infused into an area at the base of the forebrain affected by AADC deficiency known as the putamen, resulted in moderate motor performance improvement in all four children with AADC deficiency.

However, the limited motor improvements suggested gene therapy may not have covered all the putamen and left neurons that primarily produce dopamine and serotonin unaffected.

Bankiewicz’s group developed an MRI-guided infusion platform using nonhuman primates to improve control of the gene therapy delivery and visualize how the medicine distributes in the brain. This approach was then integrated into two clinical trials testing the therapy in Parkinson’s patients. 

While preliminary studies in 20 patients with AADC deficiency conducted by the team at Ohio State showed AAV2-hAADC safely and effectively restored normal dopamine levels, serotonin levels were mostly unaffected. 

The study supported by the grant will go back to animal models to use a single cannula pass to deliver the therapy into the neurons that produce serotonin, dopamine, and the related neurotransmitter norepinephrine. 

Data on safety will be collected and used to support further studies assessing this new procedure in more people with AADC deficiency.