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A Phase I/II Clinical Trial for Treatment of Aromatic L-amino Acid Decarboxylase (AADC) Deficiency Using AAV2-hAADC (AADC)

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ClinicalTrials.gov Identifier: NCT01395641
Recruitment Status : Active, not recruiting
First Posted : July 15, 2011
Last Update Posted : August 11, 2021
Information provided by (Responsible Party):
National Taiwan University Hospital

Brief Summary:
This Phase I/II trial is to prove the efficacy and safety of AAV2-hAADC to treat patients with AADC deficiency.

Condition or disease Intervention/treatment Phase
Aromatic L-amino Acid Decarboxylase (AADC) Deficiency Drug: gene therapy Phase 1 Phase 2

Detailed Description:

Aromatic L-amino acid decarboxylase (AADC) is an enzyme responsible for the final step in the synthesis of neurotransmitters dopamine and serotonin. AADC deficiency is a rare genetic disorder. Taiwanese carry a high prevalence of AADC deficiency due to the founder mutation IVS6+4 A>T, and patients usually die before the age 5-6 years due to severe motor dysfunction.

Gene therapy with adeno-associated virus (AAV) serotype 2 (AAV2) driven human AADC (hAADC) has been tested in both animal models and Phase I clinical trials of Parkinson disease. We have done a compassionate treatment of 8 patients with AADC deficiency by AAV2-hAADC and demonstrated a result that among the treated patients, 4 could stand with support, 3 could sit with support, and there was no virus-associated toxicity. The longest follow up has exceeded 4 years.

This study is to prove the safety and efficacy of AAV2-hAADC treatment for patients with Aromatic L-amino acid decarboxylase (AADC) deficiency.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 10 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I/II Clinical Trial for Treatment of Aromatic L-amino Acid Decarboxylase (AADC) Deficiency Using AAV2-hAADC
Actual Study Start Date : October 1, 2014
Estimated Primary Completion Date : December 31, 2021
Estimated Study Completion Date : December 31, 2021

Arm Intervention/treatment
Experimental: Gene therapy
Intracerebral infusion of AAV2-hAADC viral vector will be performed
Drug: gene therapy
AAV2-hAADC viral vector will be injected into bilateral putamen by stereotactic surgery.
Other Name: Intracerebral infusion of AAV2-hAADC viral vector

Primary Outcome Measures :
  1. Evaluation of therapeutic effect [ Time Frame: 12 months ]
    1. At one year post-surgery, neurotransmitter metabolites (HVA or HIAA) is detectable in CSF (higher than that at pre-surgery)
    2. At one year post-surgery, PDMS-II score is higher than that at pre-surgery, with an improvement over 10 points

Secondary Outcome Measures :
  1. Evaluation of safety and other therapeutic effects Evaluation for the treatment safety [ Time Frame: 12 months ]
    1. The absence of intracranial bleeding, which requires surgical management, after the surgery
    2. Craniotomy-induced CSF exudation
    3. The severity of post-surgery hyperactivity (if feeding is affected and then nasogastric tube is needed)
    4. Incidence of other severe adverse events (information of adverse events of all kinds and severities will be collected, including treatment-emergent adverse events).

  2. Evaluation of secondary therapeutic effects [ Time Frame: 5 years ]
    1. Weight gain
    2. Increased signal intensity of dopamine in putamen during PET imaging
    3. Increased score in other development evaluations

  3. Exploratory endpoint [ Time Frame: 5 years ]
    1. The correlation between anti-AAV2 titer and therapeutic effect
    2. The correlation between subject's age and therapeutic effect

Information from the National Library of Medicine

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Ages Eligible for Study:   24 Months and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  1. With a confirmed diagnosis of AADC, including cerebrospinal fluid analysis to show reduced levels of neurotransmitter metabolites, HVA and 5-HIAA, and higher L-Dopa, together with more than one mutation within AADC gene.
  2. Classical clinical characteristics of AADC deficiency, such as oculogyric crises, hypotonia and developmental retardation.
  3. The sick child has to be over 2 years old or a head circumference big enough for surgery.
  4. Participating patients must cooperate completely for all evaluations and examinations before, during and after the whole trial.
  5. Parents or guardians must sign to agree on this informed consent.

Exclusion criteria

  1. Significant brain structure abnormality
  2. Patients with any health or neurological doubts that may increase the risk of surgery cannot join this trial. PI has the right to evaluate the feasibility of subjects for this trial based on his/her health condition.
  3. Since high-level neutralizing antibodies may disturb the therapeutic effect of gene therapy, patients with anti-AAV2 neutralizing antibody titer over 1,200 folds or an ELISA OD over 1 cannot be enrolled into this trial.
  4. Subjects enrolled in this clinical trial cannot take any medications that may affect this trial.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01395641

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National Taiwan University Hospital
Taipei, Taiwan, 100
Sponsors and Collaborators
National Taiwan University Hospital
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Principal Investigator: Wuh-Liang Hwu, M.D., Ph.D. National Taiwan University Hospital
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: National Taiwan University Hospital
ClinicalTrials.gov Identifier: NCT01395641    
Other Study ID Numbers: NTUH-AADC-010(200802042M)
First Posted: July 15, 2011    Key Record Dates
Last Update Posted: August 11, 2021
Last Verified: November 2020
Keywords provided by National Taiwan University Hospital:
Aromatic Amino Acid Decarboxylase
Gene Therapy
Viral Vector
Gene Transfer
Aromatic L-Amino Acid Decarboxylase Deficiency