Aromatic L-amino Acid Decarboxylase Deficiency
Conditions
Keywords
AADC, AAV9, Central Nervous System (CNS) gene therapy
Brief summary
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
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. 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.
Interventions
GENETICVGN-R09b injection
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
Sponsors
Shanghai Vitalgen BioPharma Co., Ltd.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
VGN-R09b will be injected into bilateral putamen by stereotactic surgery
Eligibility
Sex/Gender
ALL
Age
18 Months to 8 Years
Healthy volunteers
No
Inclusion criteria
1. The child patient has to be ≥18 months old and \< 8 years old, and a head circumference big enough for surgery as judged by investigator. 2. Historical diagnosis of AADC deficiency with clinical symptoms consistency, AND with Molecular genetic confirmation of homozygous or compound heterozygous mutation point of IVS6+4A\>T in DDC gene. 3. With Plasma AADC activity less than or equal to 12 pmol/min/mL. 4. Motor development at baseline \<3 months (head fully uncontrollable at baseline）, and Failed to benefit from standard medical therapy (dopamine agonists, monoamine oxidase inhibitor or related form of Vitamin B6) at discretion of investigators. 5. Parent(s)/legal guardian(s) with custody of subject must give their consent for subject to enroll in the study. 6. Parent(s)/legal guardian(s) of the subject must agree to comply with the requirements of the study, including providing disease information and support disease assessment of symptoms.
Exclusion criteria
1. Intracranial neoplasm or any structural brain abnormality or lesion (e.g., severe brain atrophy, white matter degenerative changes), which, in the opinion of the study investigators, would confer excessive risk and/or inadequate potential for benefit. 2. Presence of other significant medical or neurological conditions that would create an unacceptable operative or anesthetic risk (including congenital heart disease, respiratory disease with home oxygen requirement, history of serious anesthesia complications during previous elective procedures, history of cardiorespiratory arrest), liver or renal failure, malignancy, or HIV positive. 3. Severe coagulopathy, or need for ongoing anticoagulant therapy. 4. clinically active infection or with severe infection within 12 weeks before screening (e.g. adenovirus or herpes virus, pneumonia, sepsis, central nervous system infection). 5. Previous stereotactic neurosurgery, or any gene/cell therapy. 6. Received live vaccination within 4 weeks. 7. Contraindication to sedation during surgery or imaging studies (PET or MRI).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Adverse Events (AEs), Serious Adverse Events (SAEs) | up to Week 52 | Vital signs, physical examination, laboratory test will be monitored after drug injection |
| Number of subjects who achieved motor development milestones | up to 24 months | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in brain AADC activity | up to 5 Years | Increase in signal in the putamen and nigra on Fluorodopa-PET imaging as brain AADC activity measure |
| Change in Cerebrospinal Fluid (CSF) neurotransmitter metabolite concentrations | up to 5 Years | Neurotransmitter metabolite concentrations of Homovanillic Acid/Hydroxyindoleacetic Acid (HVA/5-HIAA) would be measured |
| Change from baseline in motor function | up to 5 Years | 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. |
| Change in number of Clinical symptoms | up to 5 Years | Number of disease related symptoms |
| Viral shedding | up to 1 week | Concentrations of Viral genome in serum/urine would be measured |
| Immunogenicity after injection | up to 26 weeks | Subject number with positive antibodies of AAV9/AADC/Glial Cell Line-Derived Neurotrophic Factor (GDNF) in blood would be reported |
| Number of Adverse Events (AEs), Serious Adverse Events (SAEs) in Long-term follow-up | up to 5 Years | Drug-related AEs and SAEs would be monitored as long as 5 years after injection |
Countries
China
Contacts
PRINCIPAL_INVESTIGATORyi Wang, MD
Children's Hospital of Fudan University
PRINCIPAL_INVESTIGATORjiwen Wang, MD
Shanghai Children's Medical Center
PRINCIPAL_INVESTIGATORyunhai song, MD
Shanghai Children's Medical Center
Outcome results
None listed