Gene Therapy for Aromatic L-Amino Acid Decarboxylase Deficiency by MR-Guided Direct Delivery of AAV2-AADC to Midbrain Dopaminergic Neurons Article Swipe
Toni S. Pearson
,
Nalin Gupta
,
Waldy San Sebastián
,
Jill Imamura-Ching
,
Amy Viehoever
,
Ana Grijalvo-Perez
,
Alex J. Fay
,
Neha Seth
,
Shannon Lundy
,
Youngho Seo
,
Miguel Hernandez Pampaloni
,
Keith Hyland
,
Erin Smith
,
Gardenia deOliveiraBarbosa
,
Jill Heathcock
,
Amy J. Minnema
,
Russell R. Lonser
,
J. Bradley Elder
,
Jeffrey R. Leonard
,
Paul Larson
,
Krystof Bankiewicz
·
YOU?
·
· 2020
· Open Access
·
· DOI: https://doi.org/10.21203/rs.3.rs-73870/v1
YOU?
·
· 2020
· Open Access
·
· DOI: https://doi.org/10.21203/rs.3.rs-73870/v1
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
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Metadata
- Type
- preprint
- Language
- en
- Landing Page
- https://doi.org/10.21203/rs.3.rs-73870/v1
- https://www.researchsquare.com/article/rs-73870/v1.pdf?c=1631870970000
- OA Status
- gold
- Cited By
- 3
- References
- 23
- Related Works
- 10
- OpenAlex ID
- https://openalex.org/W4235193770
All OpenAlex metadata
Raw OpenAlex JSON
- OpenAlex ID
-
https://openalex.org/W4235193770Canonical identifier for this work in OpenAlex
- DOI
-
https://doi.org/10.21203/rs.3.rs-73870/v1Digital Object Identifier
- Title
-
Gene Therapy for Aromatic L-Amino Acid Decarboxylase Deficiency by MR-Guided Direct Delivery of AAV2-AADC to Midbrain Dopaminergic NeuronsWork title
- Type
-
preprintOpenAlex work type
- Language
-
enPrimary language
- Publication year
-
2020Year of publication
- Publication date
-
2020-09-25Full publication date if available
- Authors
-
Toni S. Pearson, Nalin Gupta, Waldy San Sebastián, Jill Imamura-Ching, Amy Viehoever, Ana Grijalvo-Perez, Alex J. Fay, Neha Seth, Shannon Lundy, Youngho Seo, Miguel Hernandez Pampaloni, Keith Hyland, Erin Smith, Gardenia deOliveiraBarbosa, Jill Heathcock, Amy J. Minnema, Russell R. Lonser, J. Bradley Elder, Jeffrey R. Leonard, Paul Larson, Krystof BankiewiczList of authors in order
- Landing page
-
https://doi.org/10.21203/rs.3.rs-73870/v1Publisher landing page
- PDF URL
-
https://www.researchsquare.com/article/rs-73870/v1.pdf?c=1631870970000Direct link to full text PDF
- Open access
-
YesWhether a free full text is available
- OA status
-
goldOpen access status per OpenAlex
- OA URL
-
https://www.researchsquare.com/article/rs-73870/v1.pdf?c=1631870970000Direct OA link when available
- Concepts
-
Dopaminergic, Aromatic L-amino acid decarboxylase, Midbrain, Dopamine, Genetic enhancement, Neuroscience, Medicine, Chemistry, Gene, Biochemistry, Biology, Central nervous systemTop concepts (fields/topics) attached by OpenAlex
- Cited by
-
3Total citation count in OpenAlex
- Citations by year (recent)
-
2023: 1, 2022: 1, 2021: 1Per-year citation counts (last 5 years)
- References (count)
-
23Number of works referenced by this work
- Related works (count)
-
10Other works algorithmically related by OpenAlex
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| abstract_inverted_index.well-tolerated | 145 |
| abstract_inverted_index.ClinicalTrials.gov | 235 |
| abstract_inverted_index.convection-enhanced | 81 |
| abstract_inverted_index.Registration:</bold> | 234 |
| abstract_inverted_index.function.<bold>Trial | 233 |
| abstract_inverted_index.<title>Abstract</title> | 0 |
| abstract_inverted_index.<bold>Background</bold>: | 1 |
| abstract_inverted_index.University.<bold>Results</bold>: | 138 |
| abstract_inverted_index.support.<bold>Conclusion</bold>: | 210 |
| abstract_inverted_index.disturbance.<bold>Objective</bold>: | 46 |
| cited_by_percentile_year.max | 94 |
| cited_by_percentile_year.min | 89 |
| corresponding_author_ids | https://openalex.org/A5047260133 |
| countries_distinct_count | 1 |
| institutions_distinct_count | 21 |
| corresponding_institution_ids | https://openalex.org/I52357470 |
| sustainable_development_goals[0].id | https://metadata.un.org/sdg/3 |
| sustainable_development_goals[0].score | 0.6600000262260437 |
| sustainable_development_goals[0].display_name | Good health and well-being |
| citation_normalized_percentile.value | 0.54517489 |
| citation_normalized_percentile.is_in_top_1_percent | False |
| citation_normalized_percentile.is_in_top_10_percent | False |