This trial includes dose-escalating part (phase 1) and dose confirming part, to prove the safety and efficacy of VGN-R09b to treat patients with severe AADC deficiency
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. VGN-R09b is a kind of Gene therapy with adeno-associated virus (AAV) serotype 9 (AAV9) driven human AADC (hAADC) being injected directly into putamen. This is an open, dose-escalating and dose confirming study. The sponsor plans to explore two dose levels (6.0×1011vg and 1.28×1012vg) in dose-escalating phase (three subjects each cohort), then plans to have 10 subjects enrolled for dose confirmation phase. This study is to give evidence for the safety and efficacy of VGN-R09b treatment for patients with severe Aromatic L-amino acid decarboxylase (AADC) deficiency.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
16
Two levels of VGN-R09b will be injected into bilateral putamen in dose-escalating phase, and one dose level will be injected in dose confirming phase
Number of Adverse Events (AEs), Serious Adverse Events (SAEs)
Vital signs, physical examination, laboratory test will be monitored after drug injection
Time frame: up to Week 52
Number of subjects who achieved motor development milestones
Four milestones, including Head control, Sit independently, Stand/stepping with support, Walk with minimal assistant, would be assessed according to definition in Peabody Developmental Motor Scale 2nd edition (PDMS-2). Each milestone would be scored as 0, 1 or 2, and score 2 means achievement of the milestone.
Time frame: up to 24 months
Change in brain AADC activity
Increase in signal in the putamen and nigra on Fluorodopa-PET imaging as brain AADC activity measure
Time frame: up to 5 Years
Change in Cerebrospinal Fluid (CSF) neurotransmitter metabolite concentrations
Neurotransmitter metabolite concentrations of Homovanillic Acid/Hydroxyindoleacetic Acid (HVA/5-HIAA) would be measured
Time frame: up to 5 Years
Change from baseline in motor function
Motor function would be assessed by Peabody Developmental Motor Scale 2nd edition (PDMS-2). The score ranges from 0 to 482, and higher score means the better in motor function.
Time frame: up to 5 Years
Change in number of Clinical symptoms
Number of disease related symptoms
Time frame: up to 5 Years
Viral shedding
Concentrations of Viral genome in serum/urine would be measured
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Time frame: up to 1 week
Immunogenicity after injection
Subject number with positive antibodies of AAV9/AADC/Glial Cell Line-Derived Neurotrophic Factor (GDNF) in blood would be reported
Time frame: up to 26 weeks
Number of Adverse Events (AEs), Serious Adverse Events (SAEs) in Long-term follow-up
Drug-related AEs and SAEs would be monitored as long as 5 years after injection
Time frame: up to 5 Years