UCL Discovery
UCL home » Library Services » Electronic resources » UCL Discovery

Aromatic L-amino acid decarboxylase deficiency: a patient-derived neuronal model for precision therapies

Rossignoli, G; Krämer, K; Lugarà, E; Alrashidi, H; Pope, S; De La Fuente Barrigon, C; Barwick, K; ... Kurian, MA; + view all (2021) Aromatic L-amino acid decarboxylase deficiency: a patient-derived neuronal model for precision therapies. Brain 10.1093/brain/awab123. (In press). Green open access

[img]
Preview
Text
Counsell_Aromatic l-amino acid decarboxylase deficiency- a patient-derived neuronal model for precision therapies_AAM.pdf - Accepted version

Download (3MB) | Preview

Abstract

Aromatic L-amino acid decarboxylase (AADC) deficiency is a complex inherited neurological disorder of monoamine synthesis which results in dopamine and serotonin deficiency. The majority of affected individuals have variable, though often severe cognitive and motor delay, with a complex movement disorder and high risk of premature mortality. For most, standard pharmacological treatment provides only limited clinical benefit. Promising gene therapy approaches are emerging, though may not be either suitable or easily accessible for all patients. In order to better characterize the underlying disease pathophysiology and guide precision therapies, we generated a patient-derived midbrain dopaminergic (mDA) neuronal model of AADC deficiency from induced pluripotent stem cells (iPSCs). The neuronal model recapitulates key disease features, including absent AADC enzyme activity and dysregulated dopamine metabolism. We observed developmental defects affecting synaptic maturation and neuronal electrical properties, which were improved by lentiviral gene therapy. Bioinformatic and biochemical analyses on recombinant AADC predicted that the activity of one variant could be improved by L-3,4-dihydroxyphenylalanine (L-DOPA) administration; this hypothesis was corroborated in the patient-derived neuronal model, where L-DOPA treatment leads to amelioration of dopamine metabolites. Our study has shown that patient-derived disease modelling provides further insight into the neurodevelopmental sequelae of AADC deficiency, as well as a robust platform to investigate and develop personalised therapeutic approaches.

Type: Article
Title: Aromatic L-amino acid decarboxylase deficiency: a patient-derived neuronal model for precision therapies
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1093/brain/awab123
Publisher version: https://doi.org/10.1093/brain/awab123
Language: English
Additional information: Copyright © The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
Keywords: Induced pluripotent stem cells, aromatic L-amino acid decarboxylase deficiency, dopaminergic neurons, neurodevelopment, personalized medicine
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Clinical and Experimental Epilepsy
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Surgery and Interventional Sci
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL EGA Institute for Womens Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL EGA Institute for Womens Health > Maternal and Fetal Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Developmental Neurosciences Dept
URI: https://discovery.ucl.ac.uk/id/eprint/10124887
Downloads since deposit
16Downloads
Download activity - last month
Download activity - last 12 months
Downloads by country - last 12 months

Archive Staff Only

View Item View Item