Subscribe to eTOC

Gene Therapy for Aromatic L-Amino Acid Decarboxylase Deficiency Appears Encouraging


CHICAGO—Two different gene therapy approaches led to improvements in motor function and other symptoms associated with aromatic L-amino acid decarboxylase (AADC) deficiency, a rare inherited disorder that causes severe motor dysfunction in infants and children, researchers reported here at the annual meeting of the Child Neurology Society.

AADC deficiency is caused by mutations in the DDC gene, which provides the instructions for construction of the AADC enzyme that creates the neurotransmitters dopamine and serotonin. Children with the disorder fail to achieve motor milestones — such as control of the head, standing, and walking — which usually manifests within their first year of life.

One research group, led by PTC Therapeutics — used a viral vector with complementary DNA encoding the AADC enzyme. The vector was first developed in Japan for trials involving Parkinson's disease; the first AADC deficiency trials were conducted in Taiwan.

In the current study, 18 children — ages 21 months to 8 years old (none of whom had head control or could sit unassisted or stand) — were given the drug with a bilateral stereotactic infusion in the putamen; the post-synaptic approach targeted an area in which dopaminergic neurons bind with other neurons.

"We believe strongly in our approach because it's based in the original Parkinson's disease trials" in which the gene therapy was first attempted, said Todd Berner, MD, head of medical affairs for PTC, who presented the findings. The anatomic location of the drug administration, the relatively large number of patients, and the length of follow-up, bode well for the approach, Dr. Berner said.

All of the patients had sustained dopamine production. Among 18 patients who were followed for two years, five had full head control, four could sit unassisted, and one could stand with support. Of eight patients evaluated after five years of treatment, four had full head control and were able to sit unassisted, and two could stand with support.

Although not all the milestones have been achieved by all patients, investigators continue to see improvements with time, Dr. Berner said.

He added that the company plans to file an application with the US Food and Drug Administration later this year or early 2019.

In a second study, researchers at University of California, San Francisco and Washington University used magnetic resonance imaging guidance to administer the vector into the substantia nigra and the ventral tegmental area of the midbrain, where the dopaminergic neurons then project out to other regions of the brain such as the basal ganglia.

"We think it's very important that we target the midbrain," said Toni Pearson, MBBS, associate professor of pediatric neurology at Washington University. "We wanted to try to re-innervate those pathways by inserting the gene into neurons that typically make and release dopamine — to be able to improve dopamine neurotransmission physiologically."

The patients who've undergone the surgery are 5 to 9 years old — older than the PTC cohort —because of the different surgical approaches and the type of brace used during the procedures.

Dr. Pearson said their procedure has been well-tolerated, with hospital stays of just three or four days.

In four of the five patients, oculogyric crises — episodes of involuntary movement of the eyes and stiffening of the body— disappeared, Dr. Pearson said.

In three patients for whom 12- to 18-month follow-up data are available, the amount of sleep per night, irritability, and excessive sweating have all improved, in some cases dramatically, she said. Motor function has improved in all patients, with variation. Approximately 18 months after the surgery, one patient with severe motor impairment at baseline can now sit by herself, eat food by mouth, speak several words, use her hands to pick things up, and stand and walk with just a bit of support, Dr. Pearson said.

Researchers are planning to do a sixth procedure by the end of the year and plan to enroll more patients at a second site starting next year.

Commenting on the two trials, Max Wiznitzer, MD, FAAN, professor of pediatrics and neurology at Case Western Reserve University School of Medicine, said the therapies have "great promise" but he cautioned that they target specific locations in the brain.

"The AADC deficiency and associated serotonin and dopamine synthesis disorder is more widespread than these locations so a 100 percent improvement is not expected," Dr. Wiznitzer said. "Caveats include concerns for infection, immune response to the viral vector, duration of the gene effect, age of treatment, and variability of the disorder depending on the specific gene variant."

Taiwanese carry a high prevalence of AADC deficiency due to a founder mutation (IVS6+4A>T) in the AADC gene. But not everyone carries the Taiwanese variant, Dr. Wiznitzer said.

Dr. Wiznitzer said he'll continue to watch for results to see the duration of effect, any long-term problems with the vector, and whether the therapies alter or improve life in a meaningful way.

Dr. Wiznitzer added that he did not think there were advantages to using one administration site or the other for the vector. "Only time will tell, which, if any, is the better choice," he said.

Dr. Berner is an employee and receives a salary from PTC Therapeutics. Dr. Wiznitzer reported no disclosures.


Chien YH, Lee NC, Tseng SH, et al. Efficacy and safety of AAV2 therapy in children with aromatic L-amino acid decarboxylase deficiency: An open-label phase 1/2 trial. Lancet Child Adolesc Health 2017; 1(4): 265-273.