AADC Gene Therapy Trials (USA & UK)

AADC deficiency is caused by mutations in a single gene called AADC. Because of these mutations patients are unable to produce two chemicals called dopamine and serotonin. These chemicals act as neurotransmitters to carry signals between nerve cells in the brain. Current treatments for AADC deficiency try to increase or replace these chemicals but do not work well for most patients and often have serious side-effects. New treatment options are desperately needed to help the patients affected by this disorder. In response to this a clinical trial of gene therapy for AADC deficiency is planned to take place at the University of California San Francisco (UCSF) and the National Institutes of Health (NIH), USA. The aim is to transfer a functional copy of the AADC gene into the specific part of the brain where AADC is normally found. This should act like a replacement for the patient’s dysfunctional gene and allow the patient to produce neurotransmitters.

The Gene Vector

The trial will make use of technology that was originally designed to treat Parkinson’s disease. A special type of virus, known as a vector, has been developed that contains the AADC gene. The vector acts as a delivery system to transfer the gene into the patient’s cells. The full name of the vector is adeno-associated virus serotype 2 (AAV2). The AAV2 vector has already been used in gene therapy trials for a number of different diseases. The AAV2 vector containing the human AADC gene is called AAV2-hAADC. The vector is manufactured in a specialist facility at the Children’s Hospital of Philadelphia. The vector is produced inside cells, purified and filtered within the facility. This facility operates to Current Good Manufacturing Practice (cGMP) standards and is regulated by the U.S. Food and Drug Administration (FDA).

The Surgery

In order for the AAV2-hAADC vector to be delivered to the correct brain cells it needs to be directly injected into a specific region of the brain. Professor Krystof Bankiewicz and his team have developed pioneering surgical techniques to ensure accurate delivery of a vector to the selected brain region. The system uses a specially designed cannula that is inserted into the brain to allow direct infusion of a liquid containing the AAV2-hAADC vector. The patient’s head is placed in a specialised stereotactic frame and cannula guide devices are attached. Real-time MRI imaging of the patient’s brain is used to map the target region, plan cannula insertion and positioning, and calculate how much vector to infuse. Brain imaging is performed throughout the surgery to guide the cannula to the target site and a special gadolinium tracer will enable the surgeons to visualise the spread of the vector. Following delivery the cannula is removed and the incision is closed by the surgeons. Following surgery the patients will be cared for and closely monitored.

The Targeted Brain Region

The nerve cells that use dopamine in the brain are organised into a series of pathways. These pathways connect one part of the brain to another with the nerve cells acting like wires between them. There are three major dopamine pathways: the mesocortical pathway, the mesolimbic pathway and the nigrostriatal pathway. The mesocortical and mesolimbic pathways both start in a brain area called the ventral tegmental area (VTA) and the nigrostriatal pathway begins in an area called the substantia nigra pars compacta (SNpc). Both the VTA and SNpc are found in an area of the brain called the mid-brain. For this reason Prof. Bankiewicz plans to target the mid-brain region in the gene therapy clinical trial for AADC deficiency. The hope is that by targeting the mid-brain all three of these pathways will receive the functional AADC gene. Additionally, previous work from the Bankiewicz lab has demonstrated that the AAV vector is able to be transported from the start of a pathway to the end (anterograde transport) but not from the end to the start (retrograde transport). By targeting the start of the dopamine pathways it is suggest that the AADC vector will be transported to the ends of the pathways and hopefully increase the effectiveness of treatment. One of the major differences between Prof. Bankiewicz’s trial and the ongoing gene therapy trial in Taiwan is the brain area that is targeted. In the Taiwanese trial they have been targeting a different area of the brain called the putamen, which is the end point of the nigrostriatal dopamine pathway.

The initial clinical trial aims to treat 12 children with AADC deficiency and the trial will be open to patients from across the world. Work is also ongoing to open a second trial site in the UK.

The AADC Research Trust is strongly supportive of this gene therapy clinical trial. The Trust awarded 45,000 USD to Prof. Krystof Bankiewicz to aid preparation of an application to the FDA for Investigational New Drug (IND) status.

Please visit this website to learn more about the Bankiewicz Laboratory:


A safety study was carried out in preparation for AADC gene therapy which is detailed in this publication:

San Sebastian, W., Kells, A. P., Bringas, J., Samaranch, L., Hadaczek, P., Ciesielska, A. and Bankiewicz, K. S. (2014). Safety and tolerability of MRI-guided infusion of AAV2-hAADC into the mid-brain of non-human primate. Molecular Therapy. Methods & Clinical Development, 3, 14049.


More information on gene therapy in Taiwan can be found in the following publication:

Hwu, W.-L., Muramatsu, S., Tseng, S.-H., Tzen, K.-Y., Lee, N.-C., Chien, Y.-H. and Wu, R.-M. (2012). Gene therapy for aromatic L-amino acid decarboxylase deficiency. Science Translational Medicine, 4, 134ra61.