Gene Therapy for the Treatment of AADC Deficiency

Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare, inherited disorder that typically appears within the first year of life. The AADC enzyme is necessary for the production of important chemical messengers in the brain and nervous system. Children with the condition experience a number of symptoms, including severe developmental delays, weak muscle tone, involuntary movements of the arms and legs, and painful seizures. Patients require lifelong care, and particularly severe cases can lead to death within the first decade of life. The lead collaborators have developed an approved gene therapy technology to restore AADC enzyme production in the brain. The purpose of this project was to correct the underlying molecular defect and support further development work to accelerate the approval of this life-saving therapy for patients.

Scientific Synopsis

AADC deficiency arises due to mutations in the dopa decarboxylase (DDC) gene. The AADC enzyme is responsible for the final step in the synthesis of the key neurotransmitters dopamine and serotonin, which are required for normal nervous system function. Symptoms and severity of disease can vary due to the specific underlying mutations that abrogate AADC enzyme function. Affected children commonly experience severe developmental delays, weak muscle tone, and involuntary movement of the limbs. Patients with severe forms of disease usually die before the age of 7, due to severe motor dysfunction, autonomic abnormalities, and secondary complications such as choking, hypoxia, aspiration, and pneumonia.

Prior to development of a gene therapy for AADC, therapeutic practice was to increase dopamine levels through inhibition of monoamine oxidase (MAO) and the direct stimulation of dopamine receptors with dopamine agonists. However, these drug therapies provide little benefit to patients. The adeno-associated virus (AAV) human AADC gene therapy (AGIL-AADC) was aimed at correcting the underlying molecular defect that leads to disease.

Work in animal models of disease and in clinical studies in Taiwan demonstrated promising safety and efficacy, including increased dopamine production, gains in motor and cognitive functions, and improved ability to interact with caregivers and engage in physical therapy.

Lead Collaborator

Agilis Biotherapeutics, Inc., Cambridge, MA
Jodi Cook, Ph.D.

Public Health Impact

This debilitating disease strikes in childhood, affects multiple aspects of the nervous system, and requires lifelong palliative care and caregiver support. Its most severe forms can lead to premature death within the first decade of life. Upstaza™ is now the first approved disease-modifying treatment for AADC deficiency.


The TRND team retrieved and organized existing data from the three clinical trials conducted in Taiwan, conducting a rigorous statistical analysis. The team completed an End-of-Phase 2 meeting with the Food and Drug Administration (FDA) to discuss the existing data. FDA agreed that the clinical package, plus key preclinical safety, biodistribution, and chemistry, manufacturing and controls data developed by TRND, were sufficient for Agilis Biotherapeutics to proceed to filing a Biologics Licensing Application (BLA) for marketing approval in the U.S. without requiring additional bridging trials.

In 2022, PTC Therapeutics, who acquired Agilis and AGIL-AADC in 2018, received market authorization by the European Commission for Upstaza™, the first approved disease-modifying treatment for AADC deficiency and the first marketed gene therapy directly infused into the brain. Subsequently, it was granted authorization by the United Kingdom’s Medicines and Healthcare Products Regulatory Agency. This TRND project is complete.