scholarly journals Safety and Improved Efficacy Outcomes in Children With AADC Deficiency Treated With Eladocagene Exuparvovec Gene Therapy: Results From Three Clinical Trials

2021 ◽  
Author(s):  
Paul Wuh- Liang Hwu ◽  
Yin- Hsiu Chien ◽  
Ni- Chung Lee ◽  
Sheng- Hong Tseng ◽  
Chun- Hwei Ta ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Body Weight ◽  
Genetic Disorder ◽  
Acid Decarboxylase ◽  
Open Label ◽  
Amino Acid Decarboxylase ◽  
Safety Population ◽  
Oculogyric Crisis ◽  
Full Head ◽  
Intent To Treat

Introduction: aromatic L-amino acid decarboxylase (AADC) deficiency, a rare genetic disorder of neurotransmitter synthesis, is characterized by motor developmental deficits and clinical features associated with the autonomic nervous system, including dyskinesia, and oculogyric crisis. Objective: To evaluate clinical outcomes in children with AADC deficiency treated with eladocagene exuparvovec, a recombinant adeno-associated virus vector containing the human cDNA encoding the AADC enzyme. Methods: In 3 open-label clinical studies, children with AADC deficiency who had no full head control and no ability to sit, stand, or walk received eladocagene exuparvovec as bilateral, intraputaminal, stereotactic infusions during a single operative session (total dose, 1.8 x 1011vg). Body weight, oculogyric crisis episodes, and adverse events (AE) were recorded. Results: In the 3 studies, patients aged 21 months to 8.5 years (N=26) received eladocagene exuparvovec, constituting the safety population. In the intent-to- treat population (N=21), mean body weight at baseline was 12.0 kg (median 10.5 kg) and increased to 15.2 kg (median 13.2 kg) at 12 months posttreatment. Frequency of oculogyric crises was improved at 12 months posttreatment. Dyskinesia was recorded as an AE in 23 patients in the safety population; most events were mild or moderate, occurred within 3 months after eladocagene exuparvovec treatment, generally responded to standard pharmacotherapy, and resolved in all patients by 10 months. Conclusions: In children with AADC deficiency who received eladocagene exuparvovec gene therapy, body weight increased and oculogyric crises and dyskinesia improved.

scholarly journals Safety of AADC Gene Therapy for Moderately Advanced Parkinson Disease: Three-Year Outcomes From the PD-1101 Trial

Neurology ◽  
2021 ◽  
pp. 10.1212/WNL.0000000000012952
Author(s):  
Chadwick W. Christine ◽  
R. Mark Richardson ◽  
Amber D. Van Laar ◽  
Marin E. Thompson ◽  
Elisabeth M. Fine ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Gene Therapy ◽  
Motor Function ◽  
Motor Fluctuations ◽  
Acid Decarboxylase ◽  
Open Label ◽  
Serious Adverse Events ◽  
Amino Acid Decarboxylase ◽  
Label Dose

Objective:To report final, 36-month safety and clinical outcomes from the PD-1101 trial of NBIb-1817 (VY-AADC01) in participants with moderately advanced Parkinson’s disease (PD) and motor fluctuations.Methods:PD-1101 was a phase 1b, open-label, dose escalation trial of VY-AADC01, an experimental AAV2 gene therapy encoding the human aromatic L-amino acid decarboxylase (AADC) enzyme. VY-AADC01 was delivered via bilateral, intraoperative MRI-guided putaminal infusions to 3 cohorts (n = 5 participants per cohort): cohort 1, ≤7.5x1011 vector genomes (vg); cohort 2, ≤1.5x1012 vg; cohort 3, ≤4.7x1012 vg.Results:No serious adverse events (SAEs) attributed to VY-AADC01 were reported. All 4 non-vector–related SAEs (atrial fibrillation and pulmonary embolism in 1 participant and 2 events of small bowel obstruction in another participant) resolved. Requirements for PD medications were reduced by 21-30% in the 2 highest dose cohorts at 36 months. Standard measures of motor function (PD diary, UPDRS III off-medication and on-medication scores), global impressions of improvement (CGI-I, PGI-I), and quality of life (PDQ-39) were stable or improved compared with baseline at 12, 24, and 36 months following VY-AADC01 administration across cohorts.Conclusions:VY-AADC01 and the surgical administration procedure were well-tolerated and resulted in stable or improved motor function and quality of life across cohorts, as well as reduced PD medication requirements in cohorts 2 and 3 over 3 years.Clinicaltrials.gov identifier: NCT01973543Classification of evidence:This study provides Class IV evidence that, in patients with moderately advanced PD and motor fluctuations, putaminal infusion of VY-AADC01 is well tolerated and may improve motor function.

Gene therapy improves brain white matter in aromatic l‐amino acid decarboxylase deficiency

2019 ◽  
Vol 85 (5) ◽  
pp. 644-652 ◽  
Author(s):  
Chih‐Hsien Tseng ◽  
Yin‐Hsiu Chien ◽  
Ni‐Chung Lee ◽  
Yung‐Chin Hsu ◽  
Shinn‐Forng Peng ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Amino Acid ◽  
White Matter ◽  
Acid Decarboxylase ◽  
Amino Acid Decarboxylase ◽  
Brain White Matter ◽  
Decarboxylase Deficiency

Reduced Immunogenicity of Intraparenchymal Delivery of Adeno-Associated Virus Serotype 2 Vectors: Brief Overview

2021 ◽  
Vol 21 ◽  
Author(s):  
Wuh-Liang Hwu ◽  
Shin-Ichi Muramatsu ◽  
Bruria Gidoni-Ben-Zeev
Keyword(s):  
Gene Therapy ◽  
Immune Response ◽  
Clinical Trial Data ◽  
Trial Data ◽  
Acid Decarboxylase ◽  
Adeno Associated Virus ◽  
Amino Acid Decarboxylase ◽  
Virus Serotype ◽  
The Brain ◽  
Decarboxylase Deficiency

: Preexisting immunity to adeno-associated virus (AAV) poses a concern in AAV vector–mediated gene therapy. Localized administration of low doses of carefully chosen AAV serotypes can mitigate the risk of an immune response. This article will illustrate the low risk of immune response to AAV serotype 2 vector–mediated gene therapy to the brain with support from clinical trial data in aromatic L-amino acid decarboxylase deficiency and Parkinson disease.

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 Gene Therapy for Aromatic L-Amino Acid Decarboxylase Deficiency

2012 ◽  
Vol 4 (134) ◽  
pp. 134ra61-134ra61 ◽  
Author(s):  
W.-L. Hwu ◽  
S.-i. Muramatsu ◽  
S.-H. Tseng ◽  
K.-Y. Tzen ◽  
N.-C. Lee ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Amino Acid ◽  
Acid Decarboxylase ◽  
Amino Acid Decarboxylase ◽  
Decarboxylase Deficiency

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

Clinical Profile and Outcome of Indian Children with Aromatic L-Amino Acid Decarboxylase Deficiency: A primary CSF Neurotransmitter Disorder Mimicking as Dyskinetic Cerebral Palsy

2020 ◽  
Author(s):  
Vykuntaraju K. Gowda ◽  
Hemadri Vegda ◽  
Balamurugan B. Nagarajan ◽  
Sanjay K. Shivappa
Keyword(s):  
Amino Acid ◽  
Sleep Disturbance ◽  
Age Of Onset ◽  
Tertiary Care ◽  
Acid Decarboxylase ◽  
Care Hospital ◽  
Intermittent Fever ◽  
Indian Children ◽  
Amino Acid Decarboxylase ◽  
Oculogyric Crisis

AbstractAromatic L-amino acid decarboxylase (AADC) deficiency is a disorder of neurotransmitter synthesis. It presents with psychomotor delay, dystonia, oculogyric crisis, and autonomic features. There is paucity of literature on this disorder. Hence, we are reporting this series with an objective to study profile and outcome of Indian children with AADC deficiency. In this retrospective review, all case records of genetically confirmed cases of AADC deficiency at the pediatric neurology department in a tertiary care hospital, from March 2014 to March 2020, were analyzed. The data were extracted in a predesigned proforma and analyzed. Out of seven cases, five were males. Median age of onset of symptoms was 4 months but median age of diagnosis was 12 months. All of them had developmental delay, oculogyric crisis, dystonia, increased sweating, intermittent fever, feeding and sleep disturbance, irritability, failure to thrive, axial hypotonia with dyskinetic quadriparesis, and normal magnetic resonance imaging (MRI) of brain and electroencephalogram (EEG). All of them were treated with pyridoxal 5-phosphate, trihexyphenidyl and pramipexole and six cases, in addition, were given bromocriptine. One case was additionally treated with selegiline. One case showed good improvement, five showed partial improvement, and one case expired. In conclusion, AADC deficiency should be suspected in any child with dyskinetic quadriparesis, oculogyric crisis, autonomic disturbances like increased sweating, intermittent fever, and sleep disturbance with normal neuroimaging.

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