| Autor: |
Waldy San Sebastian, Adrian P Kells, John Bringas, Lluis Samaranch, Piotr Hadaczek, Agnieszka Ciesielska, Michael J Macayan, Phillip J Pivirotto, John Forsayeth, Sheryl Osborne, J Fraser Wright, Foad Green, Gregory Heller, Krystof S Bankiewicz |
| Jazyk: |
angličtina |
| Rok vydání: |
2014 |
| Předmět: |
|
| Zdroj: |
Molecular Therapy: Methods & Clinical Development, Vol 1, Iss C (2014) |
| Druh dokumentu: |
article |
| ISSN: |
2329-0501 |
| DOI: |
10.1038/mtm.2014.49 |
| Popis: |
Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare, autosomal-recessive neurological disorder caused by mutations in the DDC gene that leads to an inability to synthesize catecholamines and serotonin. As a result, patients suffer compromised development, particularly in motor function. A recent gene replacement clinical trial explored putaminal delivery of recombinant adeno-associated virus serotype 2 vector encoding human AADC (AAV2-hAADC) in AADC-deficient children. Unfortunately, patients presented only modest amelioration of motor symptoms, which authors acknowledged could be due to insufficient transduction of putamen. We hypothesize that, with the development of a highly accurate MRI-guided cannula placement technology, a more effective approach might be to target the affected mid-brain neurons directly. Transduction of AADC-deficient dopaminergic neurons in the substantia nigra and ventral tegmental area with locally infused AAV2-hAADC would be expected to lead to restoration of normal dopamine levels in affected children. The objective of this study was to assess the long-term safety and tolerability of bilateral AAV2-hAADC MRI-guided pressurized infusion into the mid-brain of nonhuman primates. Animals received either vehicle, low or high AAV2-hAADC vector dose and were euthanized 1, 3, or 9 months after surgery. Our data indicate that effective mid-brain transduction was achieved without untoward effects. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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