A gene therapy approach to Childhood Parkinsonism

• Main Author: Ng, J.
• Other Authors: Waddington, S. ; Kurian, M. A. ; Rahim, A.
• Published: University College London (University of London) 2017
• Subjects: 610
• Online Access: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.746502

Dopamine transporter deficiency syndrome is an inherited primary neurotransmitter disease caused by loss of function mutations in the Dopamine transporter (DAT). DAT is key to dopamine homeostasis and termination of dopamine neurotransmission and recycling. The condition was characterised clinically with infantile onset hyperkinetic dystonic movement disorder that progresses to Parkinsonism. The patients do not respond to any pharmacological and surgical treatments and a third die by mid-adolescence. In this thesis, I describe a new cohort of patients with Dopamine transporter deficiency that include atypical clinical features and identification of seven novel missense mutations that were studied in vitro elucidating phenotype to genotype correlation. These patients were also unresponsive to currently available treatments and so there is a priority to develop new therapeutics such as gene therapy towards clinical translation for this untreatable monogenic disorder. Adeno-associated virus (AAV) gene therapy is now considered a realistic treatment following clinical trials in Parkinson’s disease and other childhood neurotransmitters disorders (aromatic l-amino decarboxylase deficiency). The main theme of this thesis covers the development of preclinical AAV gene therapy for Dopamine transporter deficiency syndrome using the DAT knockout mouse model. This encompasses the characterisation of the DAT knockout as a model for Dopamine Transporter deficiency syndrome and design of a preclinical gene therapy vector. The final chapter details AAV mediated human DAT gene therapy treatment of the neonatal DAT knockout mouse.