Clinical trial NCT01395641: A Phase I/II Clinical Trial for Treatment of Aromatic L-amino Acid Decarboxylase (AADC) Deficiency Using AAV2-hAADC
Official title: A Phase I/II Clinical Trial for Treatment of Aromatic L-amino Acid Decarboxylase (AADC) Deficiency Using AAV2-hAADC
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Aromatic L-amino Acid Decarboxylase (AADC) Deficiency
Keywords: Aromatic Amino Acid Decarboxylase
AADC
DDC
Gene Therapy
AAV2-AADC
Viral Vector
Gene Transfer
Aromatic L-Amino Acid Decarboxylase Deficiency
Lead sponsor: National Taiwan University Hospital
Sponsor class: OTHER
Collaborators: name: PTC Therapeutics
First posted: 2011-07-15
Enrollment: 10
Sex: ALL
Minimum age (years): 24
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Evaluation of therapeutic effect
timeFrame: 12 months
Secondary outcomes:
measure: Evaluation of safety and other therapeutic effects Evaluation for the treatment safety
timeFrame: 12 months
measure: Evaluation of secondary therapeutic effects
timeFrame: 5 years
measure: Exploratory endpoint
timeFrame: 5 years
Other outcomes:
Locations:
city: Taipei
country: Taiwan
facility: National Taiwan University Hospital
Study officials:
affiliation: National Taiwan University Hospital
name: Wuh-Liang Hwu, M.D., Ph.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Tai CH, Lee NC, Chien YH, Byrne BJ, Muramatsu SI, Tseng SH, Hwu WL. Long-term efficacy and safety of eladocagene exuparvovec in patients with AADC deficiency. Mol Ther. 2022 Feb 2;30(2):509-518. doi: 10.1016/j.ymthe.2021.11.005. Epub 2021 Nov 8.
citation: Chien YH, Lee NC, Tseng SH, Tai CH, Muramatsu SI, Byrne BJ, Hwu WL. Efficacy and safety of AAV2 gene therapy in children with aromatic L-amino acid decarboxylase deficiency: an open-label, phase 1/2 trial. Lancet Child Adolesc Health. 2017 Dec;1(4):265-273. doi: 10.1016/S2352-4642(17)30125-6. Epub 2017 Oct 23.