scholarly journals Gene therapy for aromatic L-amino acid decarboxylase deficiency by MR-guided direct delivery of AAV2-AADC to midbrain dopaminergic neurons

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Toni S. Pearson ◽  
Nalin Gupta ◽  
Waldy San Sebastian ◽  
Jill Imamura-Ching ◽  
Amy Viehoever ◽  
...  
Keyword(s):  
Amino Acid ◽  
Motor Function ◽  
Viral Vector ◽  
Genetic Disorder ◽  
Dopamine Metabolism ◽  
Acid Decarboxylase ◽  
Convection Enhanced Delivery ◽  
Amino Acid Decarboxylase ◽  
Post Surgery ◽  
Midbrain Dopaminergic Neurons

AbstractAromatic L-amino acid decarboxylase (AADC) deficiency is a rare genetic disorder characterized by deficient synthesis of dopamine and serotonin. It presents in early infancy, and causes severe developmental disability and lifelong motor, behavioral, and autonomic symptoms including oculogyric crises (OGC), sleep disorder, and mood disturbance. We investigated the safety and efficacy of delivery of a viral vector expressing AADC (AAV2-hAADC) to the midbrain in children with AADC deficiency (ClinicalTrials.gov Identifier NCT02852213). Seven (7) children, aged 4–9 years underwent convection-enhanced delivery (CED) of AAV2-hAADC to the bilateral substantia nigra (SN) and ventral tegmental area (VTA) (total infusion volume: 80 µL per hemisphere) in 2 dose cohorts: 1.3 × 1011 vg (n = 3), and 4.2 × 1011 vg (n = 4). Primary aims were to demonstrate the safety of the procedure and document biomarker evidence of restoration of brain AADC activity. Secondary aims were to assess clinical improvement in symptoms and motor function. Direct bilateral infusion of AAV2-hAADC was safe, well-tolerated and achieved target coverage of 98% and 70% of the SN and VTA, respectively. Dopamine metabolism was increased in all subjects and FDOPA uptake was enhanced within the midbrain and the striatum. OGC resolved completely in 6 of 7 subjects by Month 3 post-surgery. Twelve (12) months after surgery, 6/7 subjects gained normal head control and 4/7 could sit independently. At 18 months, 2 subjects could walk with 2-hand support. Both the primary and secondary endpoints of the study were met. Midbrain gene delivery in children with AADC deficiency is feasible and safe, and leads to clinical improvements in symptoms and motor function.

scholarly journals Gene Therapy for Aromatic L-Amino Acid Decarboxylase Deficiency by MR-Guided Direct Delivery of AAV2-AADC to Midbrain Dopaminergic Neurons

2020 ◽  
Author(s):  
Toni Pearson ◽  
Nalin Gupta ◽  
Waldy San Sebastian ◽  
Jill Imamura-Ching ◽  
Amy Viehoever ◽  
...  
Keyword(s):  
Amino Acid ◽  
San Francisco ◽  
Viral Vector ◽  
Genetic Disorder ◽  
Dopamine Metabolism ◽  
Acid Decarboxylase ◽  
Convection Enhanced Delivery ◽  
Amino Acid Decarboxylase ◽  
Post Surgery ◽  
The Ohio State University

Abstract Background: Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare genetic disorder characterized by deficient synthesis of dopamine and serotonin. It presents in early infancy, and causes severe developmental disability and lifelong motor, behavioral, and autonomic symptoms including oculogyric crises (OGC), sleep disorder, and mood disturbance.Objective: We investigated the safety and efficacy of delivery of a viral vector expressing AADC (AAV2-hAADC) to the midbrain in children with AADC deficiency. Design, Setting and Participants: Seven (7) children, aged 4-9 years underwent convection-enhanced delivery (CED) of AAV2-hAADC to the bilateral substantia nigra (SN) and ventral tegmental area (VTA) (total infusion volume: 80 µL per hemisphere) in 2 dose cohorts: 1.3 x 1011 vg (n=3), and 4.2 x 1011 vg (n=4). Six (6) subjects were treated at UCSF Benioff Children’s Hospital in San Francisco and 1 at The Ohio State University.Results: Direct bilateral infusion of AAV2-hAADC was well-tolerated and achieved target coverage of 98% and 70% of the SN and VTA, respectively. Dopamine metabolism was increased in all subjects and FDOPA uptake was enhanced within the midbrain and the striatum. OGC resolved completely in 6 of 7 subjects by Month 3 post-surgery. Eighteen (18) months after surgery (n=5), 4/5 subjects gained the ability to sit independently and 2/5 could walk with 2-hand support.Conclusion: Midbrain gene delivery in children with AADC deficiency is feasible and safe, and leads to substantial clinical improvements in symptoms and motor function.Trial Registration: ClinicalTrials.gov Identifier NCT02852213

scholarly journals Case report: discovery of 2 gene variants for aromatic L-amino acid decarboxylase deficiency in 2 African American siblings

BMC Neurology ◽  
2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Berrin Monteleone ◽  
Keith Hyland
Keyword(s):  
African American ◽  
Amino Acid ◽  
Viral Vector ◽  
Genetic Disorder ◽  
Plasma Metabolites ◽  
Acid Decarboxylase ◽  
Gene Variants ◽  
African American Female ◽  
Amino Acid Decarboxylase ◽  
Slight Elevation

Abstract Background Aromatic l-amino acid decarboxylase (AADC) deficiency is a rare genetic disorder with heterogeneous phenotypic spectrum resulting from disease-causing variants in the dopa decarboxylase (DDC) gene. Consensus guidelines recommend dopamine agonists, monoamine oxidase inhibitors, and other symptomatic treatments, but most patients have an unrelenting disease course with no response to these therapies. Case presentation We describe 2 African American siblings with AADC deficiency and identify 2 DDC gene variants not previously associated with the disorder. The patients were evaluated for cognitive and neurologic impairments. Diagnosis of AADC deficiency was initially based on evaluation of urine and plasma metabolites, followed by targeted DDC gene sequencing. The first patient, a firstborn African American female, had moderate elevations of vanillactic and vanilpyruvic acids, and slight elevation of N-acetylvanilalanine in urine. The second patient, an African American female and younger sibling of the first patient, had low AADC enzyme activity and elevated 3-O-methyldopa levels in plasma. Genetic testing confirmed that both siblings possessed the same 2 DDC gene variants, which were identified as NM_000790.3: c.48C > A (p.Tyr16Ter) and NM_000790.3: c.116G > C (p.Arg39Pro). Conclusions This report describes 2 previously unknown patients with AADC deficiency and confirmed the presence of 2 DDC gene variants not previously associated with this disorder. Further research is needed to identify disease-modifying treatments for this devastating neurometabolic disorder. Gene therapy with a recombinant adeno-associated viral vector serotype 2 carrying the gene for the human AADC protein (AAV2-hAADC) is currently in clinical development.

scholarly journals Microdialysis with Radiometric Monitoring of L-[β-11C]DOPA to Assess Dopaminergic Metabolism: Effect of Inhibitors of L-Amino Acid Decarboxylase, Monoamine Oxidase, and Catechol-O-Methyltransferase on Rat Striatal Dialysate

2010 ◽  
Vol 31 (1) ◽  
pp. 124-131 ◽  
Author(s):  
Maki Okada ◽  
Ryuji Nakao ◽  
Rie Hosoi ◽  
Ming-Rong Zhang ◽  
Toshimitsu Fukumura ◽  
...  
Keyword(s):  
Amino Acid ◽  
Monoamine Oxidase ◽  
Dopamine Metabolism ◽  
Rat Striatum ◽  
Acid Decarboxylase ◽  
Comt Inhibitors ◽  
Amino Acid Decarboxylase ◽  
Metabolite Profiles ◽  
Radiometric Detection ◽  
Effect Of Inhibitors

The catecholamine, dopamine (DA), is synthesized from 3,4-dihydroxy-L-phenylalanine (L-DOPA) by aromatic L-amino acid decarboxylase (AADC). Dopamine metabolism is regulated by monoamine oxidase (MAO) and catechol- O-methyltransferase (COMT). To measure dopaminergic metabolism, we used microdialysis with radiometric detection to monitor L-[β-11C]DOPA metabolites in the extracellular space of the rat striatum. We also evaluated the effects of AADC, MAO, and COMT inhibitors on metabolite profiles. The major early species measured after administration of L-[β-11C]DOPA were [11C]3,4-dihydroxyphenylacetic acid ([11C]DOPAC) and [11C]homovanillic acid ([11C]HVA) in a 1:1 ratio, which shifted toward [11C]HVA with time. An AADC inhibitor increased the uptake of L-[β-11C]DOPA and L-3- O-methyl-[11C]DOPA and delayed the accumulation of [11C]DOPAC and [11C]HVA. The MAO and COMT inhibitors increased the production of [11C]3-methoxytyramine and [11C]DOPAC, respectively. These results reflect the L-DOPA metabolic pathway, suggesting that this method may be useful for assessing dopaminergic metabolism.

scholarly journals Aromatic L-amino Acid Decarboxylase (AADC) deficiency: results from an Italian modified Delphi consensus

2021 ◽  
Vol 47 (1) ◽  
Author(s):  
Carlo Fusco ◽  
◽  
Vincenzo Leuzzi ◽  
Pasquale Striano ◽  
Roberta Battini ◽  
...  
Keyword(s):  
Amino Acid ◽  
Diagnostic Delay ◽  
Steering Committee ◽  
Outcome Data ◽  
Diagnosis And Treatment ◽  
Acid Decarboxylase ◽  
Delphi Consensus ◽  
Amino Acid Decarboxylase ◽  
Modified Delphi ◽  
Number Of Patients

Abstract Background Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare and underdiagnosed neurometabolic disorder resulting in a complex neurological and non-neurological phenotype, posing diagnostic challenges resulting in diagnostic delay. Due to the low number of patients, gathering high-quality scientific evidence on diagnosis and treatment is difficult. Additionally, based on the estimated prevalence, the number of undiagnosed patients is likely to be high. Methods Italian experts in AADC deficiency formed a steering committee to engage clinicians in a modified Delphi consensus to promote discussion, and support research, dissemination and awareness on this disorder. Five experts in the field elaborated six main topics, each subdivided into 4 statements and invited 13 clinicians to give their anonymous feedback. Results 100% of the statements were answered and a consensus was reached at the first round. This enabled the steering committee to acknowledge high rates of agreement between experts on clinical presentation, phenotypes, diagnostic work-up and treatment strategies. A research gap was identified in the lack of standardized cognitive and motor outcome data. The need for setting up an Italian working group and a patients’ association, together with the dissemination of knowledge inside and outside scientific societies in multiple medical disciplines were recognized as critical lines of intervention. Conclusions The panel expressed consensus with high rates of agreement on a series of statements paving the way to disseminate clear messages concerning disease presentation, diagnosis and treatment and strategic interventions to disseminate knowledge at different levels. Future lines of research were also identified.

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