Institutional Research Information Service
UCL Logo
Please report any queries concerning the funding data grouped in the sections named "Externally Awarded" or "Internally Disbursed" (shown on the profile page) to your Research Finance Administrator. Your can find your Research Finance Administrator at https://www.ucl.ac.uk/finance/research/rs-contacts.php by entering your department
Please report any queries concerning the student data shown on the profile page to:

Email: portico-services@ucl.ac.uk

Help Desk: http://www.ucl.ac.uk/ras/portico/helpdesk
Publication Detail
Aromatic L-amino acid decarboxylase deficiency: a patient-derived neuronal model for precision therapies
  • Publication Type:
    Journal article
  • Publication Sub Type:
  • Authors:
    Rossignoli G, Krämer K, Lugarà E, Alrashidi H, Pope S, De La Fuente Barrigon C, Barwick K, Bisello G, Ng J, Counsell J, Lignani G, Heales SJR, Bertoldi M, Barral S, Kurian MA
  • Publication date:
  • Journal:
  • Status:
  • Country:
  • PII:
  • Language:
  • Keywords:
    Induced pluripotent stem cells, aromatic L-amino acid decarboxylase deficiency, dopaminergic neurons, neurodevelopment, personalized medicine
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.
Publication data is maintained in RPS. Visit https://rps.ucl.ac.uk
 More search options
UCL Researchers Show More
Developmental Neurosciences Dept
ICH - Laboratory Management
Department of Targeted Intervention
Genetics & Genomic Medicine Dept
Developmental Neurosciences Dept
Clinical & Experimental Epilepsy
UCL Queen Square Institute of Neurology
Maternal & Fetal Medicine
Neurodegenerative Diseases
University College London - Gower Street - London - WC1E 6BT Tel:+44 (0)20 7679 2000

© UCL 1999–2011

Search by