Clinical Investigation

Gene Therapy for Aromatic l-Amino Acid Decarboxylase Deficiency
Primary investigator: Wuh-Liang Hwu

National Taiwan University Hospital, Taipei, Taiwan


What is aromatic L-amino acid decarboxylase (AADC) deficiency

  1. It is an inherited metabolic disease caused by mutations in the DDC gene
  2. This is a very rare disorder but its incidence is higher in Taiwan than in western countries

Clinical Manifestations of AADC deficiency

  1. Severe dopamine and serotonin deficiency
  2. Hypotonia, Oculogyric crisis, Dystonia
  3. Autonomic system dysfunction
  4. Early death
  5. Poor response to medications

Principle of gene therapy for AADC deficiency

  1. A adeno-associated virus serotype 2 (AAV2) viral expressing the human AADC cDNA (AAV2-hAADC)
  2. The vector was injected into bilateral putamen of patients by stereotactic surgery
  3. AAV2-hAADC produces dopamine in putamen and relieve the motor disability of patients

 

Method of gene delivery

  1. The surgery is very similar that for deep brain stimulation
  2. Two burr holes will be made on each side of the skull
  3. Through each burr hole, each putamen will be injected twice
  4. This is a one-time treatment

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Figure 1: Explanation of the stereotactic surgery. Left panel illustrates the four injections through two burr holes. Right panel indicates the injection site, the putamen.

 

Clinical trials

The Phase 1/II trial (NCT01395641): Completed, this trial treated 10 patients. All patients revealed improved in motor function and decrease in the severity of oculogyric crisis attacks.


Figure 2: FDOPA positron emission tomography (PET) study revealed the visualization of bilateral putamens after gene therapy.

 

The Phase IIb trial (NCT02926066): Ongoing, this trial includes two-dosages in patients younger than 3 years.


Achievements of the clinical trial

  1. Technology transfer: Agilis Biotherapeutics, LLC , Dec 2015
  2. Orphan Drug Designation, FDA, June 2016
  3. Rare Pediatric Disease (RPD) designation, FDA, Nov 2016
  4. Orphan Medicinal Product (OMP) designation, EU, Dec 2016

Collaborators

  1. Jichi Medical University, Japan
  2. Powell Gene Therapy Center, University of Florida, USA

Publications

Science Translational Medicine 2012 May 16;4(134):134ra61. ​