a trial to evaluate safety and efficacy of a product named vgn-r09b in severe aadc deficiency

Conditions: Aromatic L-amino Acid Decarboxylase Deficiency

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

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.

Eligibility criteria:
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).

Keywords: aadc aav9 central nervous system (cns) gene therapy