AADC Deficiency
All of our projects depend on the creation and advancement of direct infusion of drugs and therapies into the brain. We have developed a technique in which lipid-like nanoparticles and other therapeutic agents can be infused directly into brain tumors to give enhanced drug efficacy with reduced side effects. For many years, and continuing still, we have been working on development of direct drug delivery into the brain including cell transplantation, gene transfer and growth factor infusions for Parkinson's disease. Through gene therapy, we are working to eliminate this inherited lipid storage disorder by restoring the activity of the gene responsible for Niemann-Pick disease, acid sphingomyelinase. Prolonged treatment of Parkinson’s disease with L-DOPA may result in a characteristic movement disorder known as dyskinesia. By studying the effects of L-DOPA on the brain, we are developing gene therapy solutions to treat L-DOPA-induced dyskinesias. Using our image-guided delivery techniques AADC activity in the brain, important in the synthesis of several neurotransmitters, may be restored by gene therapy in patients lacking the gene for AADC.

Picture of AADC transduction
An image showing expression of the AADC activity in the primate brain using image-guided delivery of AAV2-AADC.
The AADC is
and tyrosine hydroxylase is
. We believe that a similar approach could be used for the correction of the genetic deficit in children with AADC deficiency.

What is AADC Deficiency?

Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare debilitating recessive genetic disorder in which mutations in the AADC gene lead to an inability to synthesize catecholamines [norepinephrine, dopamine] and serotonin. As a result, afflicted children suffer severe movement and affective disorders with a consequently curtailed, difficult life. Patients suffer a severe neurometabolic disorder with developmental delay, abnormal movements, oculogyric crises and vegetative symptoms. The most prominent symptom, however, is a severe Parkinsonian movement disorder. Fortunately, this autosomal recessive disorder is extremely rare; approximately 20 to 30 cases have been identified worldwide. Despite the severity of the disease, subjects typically survive to become adults. Because the disease is caused by a profound loss of functional AADC, gene replacement is seen as one of the most desirable and potentially transformative candidate therapies.

Our approach

In recent years, use of a gene therapy vector encoding AADC has entered the clinic for the treatment of Parkinson’s disease where progressive loss of endogenous AADC plays an important role in blunting responses to the mainstay drug, L-DOPA. The recently completed Phase 1 study has demonstrated that an adeno-associated virus-based vector encoding human AADC (AAV2-hAADC) appears to be safe in PD patients. It seems reasonable, therefore, to consider employing the same vector for genetic AADC deficiency. By delivering AAV2-hAADC to the ventral tegmental area (VTA) and substantia nigra pars compacta (SNc) of afflicted children, we believe that we will substantially rescue dopamine and serotonin biosynthesis and, we hope, substantially improve the quality of life of these patients.

How our research helps

The proposed treatment for AADC deficiency incorporates the most advanced gene delivery technology available. Precise MRI-guided delivery will afford absolute control over infusions in a manner not previously available to clinicians. We envisage the rapid emergence of this technology as a standard medical procedure for neurological gene therapy. Our ability to target any part of the brain and to control visually the infusion parameters intra-operatively provides a tremendous asset to clinicians.