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

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

Study Overview

• Status: Completed
• Conditions: Aromatic L-amino Acid Decarboxylase (AADC) Deficiency
• Intervention / Treatment: Drug: gene therapy

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.

• Study Type: Interventional
• Enrollment (Actual): 10
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Taiwan
  • Taipei, Taiwan, 100
    • National Taiwan University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years and older (ADULT, OLDER_ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / 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 Names: Intracerebral infusion of AAV2-hAADC viral vector

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Evaluation of therapeutic effect	At one year post-surgery, neurotransmitter metabolites (HVA or HIAA) is detectable in CSF (higher than that at pre-surgery); At one year post-surgery, PDMS-II score is higher than that at pre-surgery, with an improvement over 10 points	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Evaluation of safety and other therapeutic effects Evaluation for the treatment safety	The absence of intracranial bleeding, which requires surgical management, after the surgery; Craniotomy-induced CSF exudation; The severity of post-surgery hyperactivity (if feeding is affected and then nasogastric tube is needed); Incidence of other severe adverse events (information of adverse events of all kinds and severities will be collected, including treatment-emergent adverse events).	12 months
Evaluation of secondary therapeutic effects	Weight gain; Increased signal intensity of dopamine in putamen during PET imaging; Increased score in other development evaluations	5 years
Exploratory endpoint	The correlation between anti-AAV2 titer and therapeutic effect; The correlation between subject's age and therapeutic effect	5 years

Collaborators and Investigators

• Sponsor: National Taiwan University Hospital
• Collaborators: PTC Therapeutics

Publications and helpful links

General Publications

• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (ACTUAL): October 22, 2014
• Primary Completion (ACTUAL): December 18, 2020
• Study Completion (ACTUAL): March 7, 2022

Study Registration Dates

• First Submitted: June 12, 2011
• First Submitted That Met QC Criteria: July 14, 2011
• First Posted (ESTIMATE): July 15, 2011

Study Record Updates

• Last Update Posted (ACTUAL): February 10, 2023
• Last Update Submitted That Met QC Criteria: February 8, 2023
• Last Verified: November 1, 2022

More Information

Terms related to this study

• Keywords: Gene Therapy; Viral Vector; Gene Transfer; Aromatic Amino Acid Decarboxylase; AADC; DDC; AAV2-AADC; Aromatic L-Amino Acid Decarboxylase Deficiency
• Other Study ID Numbers: NTUH-AADC-010(200802042M)