Gene Therapy

Aromatic L-amino acid decarboxylase (AADC) deficiency is a genetic disease that affects the communication between the brain and other parts of the body.

AADC deficiency is caused by mutations in the dopa decarboxylase (DDC) gene, which provides instructions to build the AADC enzyme.

The AADC enzyme performs the last step in the production of the neurotransmitters or cell-signaling molecules dopamine and serotonin, which are required for the communication between nerve cells in the brain and the rest of the body. Mutations in the DDC gene reduce the production of the AADC enzyme or decrease its activity, leading to lower levels of dopamine and serotonin. As a consequence, AADC deficiency patients experience symptoms of motor and autonomic dysfunction.

No cure is available for AADC deficiency but treatments can help manage the symptoms. A promising approach is gene therapy, which is being investigated in clinical trials.

How does gene therapy work?

Gene therapy aims to restore the function of a defective gene. This is usually done by delivering a functional copy of the gene to the cells that need the protein that the gene encodes for.

Alternatively, gene therapy may intervene in the gene expression process, thereby correcting the problem that is caused by the mutation. Gene expression is the process by which information from a gene is used to produce a functional gene product.

Gene therapy approaches for AADC deficiency

Two primary gene therapy approaches are currently being investigated for AADC deficiency: GT-AADC is being tested in clinical trials, and U1 snRNA is at the preclinical stage.


PTC-AADC gene therapy was initially developed by Agilis Biotherapeutics, which was acquired by PTC Therapeutics in July 2018. The therapy uses adenoviral vectors to deliver functional copies of the DDC gene to a region in the brain that controls movement, the so-called putamen. Adenoviral vectors are a standard tool in gene therapy and make use of the ability of viruses to inject genetic material into cells.

The delivery of the viral vectors to the putamen requires minimally-invasive stereotactic brain surgery. Because the therapy corrects AADC levels only in the putamen and not in other brain regions, it targets mainly motor symptoms.

PTC-AADC gene therapy was assessed in a Phase 1/2 clinical trial (NCT01395641) in 10 patients, from 2 to 8 years old, and another Phase 1/2 clinical trial in six patients, 4 to 19 years old. The therapy was found to markedly improve motor function, and language and cognitive abilities.

PTC Therapeutics plans to seek approval for the treatment in both the U.S. and Europe.

Although PTC-AADC gene therapy is a promising therapeutic approach for the treatment of AADC deficiency, it has some drawbacks. The first is that the delivery of the DDC gene requires surgery. The second is that the treatment is confined to one region in the brain. The goal is to develop a gene therapy that does not require surgery, and that allows a broader distribution of the healthy DDC gene in the brain.

U1 snRNA

The process of protein production from a gene involves an intermediate molecule called a messenger RNA. Messenger RNA consists of exons and introns. Exons provide instructions to build the protein, and introns are intervening regions in between exons that need to be removed before the production of the protein starts. The removal of introns is known as splicing.

One kind of mutation that occurs in AADC deficiency is a so-called splicing mutation. A splicing mutation is characterized by the insertion of nucleotides (building blocks of DNA), between an exon and an intron, thereby removing the splicing site. As a result, the intron is not removed, which causes the formation of an abnormal protein.

The molecules that perform splicing are small nuclear RNAs (snRNAs). U1 snRNA is the first snRNA to be recruited to the splicing site during the intron removal process. U1 snRNA gene therapy involves a modified U1 snRNA that can recognize the mutated splicing site so that the intron is correctly removed and a functional protein is produced.

U1 snRNA gene therapy has been tested in preclinical animal studies but further research is necessary before it can proceed to human clinical trials.


Last updated: Sept. 10, 2019.


AADC News is strictly a news and information website about the disease. It does not provide medical advice, diagnosis, or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified healthcare providers with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website.