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Therapeutics for Rare and Neglected Diseases

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. There are no approved treatments for AADC deficiency. The lead collaborators are developing a gene therapy technology to restore AADC enzyme production in the brain. The purpose of this project is to 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.

There are no approved therapies for the treatment of AADC deficiency. Current practice is to increase dopamine levels through inhibition of monoamine oxidase (MAO) and direct stimulation of dopamine receptors with dopamine agonists. However, these drug therapies provide little benefit to patients. The present adeno-associated virus (AAV) human AADC gene therapy (AGIL-AADC) is aimed at correcting the underlying molecular defect that leads to disease. Work in animal models of disease and in clinical studies in Taiwan has 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

There are no approved treatments for AADC deficiency. 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.

Outcomes

The TRND project team has conducted a rigorous gap analysis to determine the project plan. TRND scientists are conducting a number of activities to support product development for AGIL-AADC. These include epidemiological studies, nonclinical safety studies, and manufacture of clinical-grade material.

Last updated: 09-11-2017
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