Novel therapeutic approaches for childhood parkinsonism

Abstract Background Dopamine transporter deficiency syndrome (DTDS) is a primary neurotransmitter disorder caused by loss-of-function mutations in SLC6A3 , which encodes the dopamine transporter (DAT). The syndrome is characterised by progressive infantile-onset dystonia-parkinsonism with raised dop...

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Published in:The Lancet (British edition) 2016-02, Vol.387, p.S77-S77
Main Authors: Ng, Joanne, Dr, Zhen, Juan, PhD, Meyer, Esther, PhD, Erreger, Kevin, PhD, Pope, Simon, PhD, Borck, Guntrum, Prof, Heales, Simon J H R, Prof, Reith, Maarten E A, Prof, Rahim, Ahad A, PhD, Waddington, Simon N, PhD, Kurian, Manju A, PhD
Format: Article
Language:English
Subjects:
Adeno-associated virus
Internal Medicine
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Summary:Abstract Background Dopamine transporter deficiency syndrome (DTDS) is a primary neurotransmitter disorder caused by loss-of-function mutations in SLC6A3 , which encodes the dopamine transporter (DAT). The syndrome is characterised by progressive infantile-onset dystonia-parkinsonism with raised dopamine metabolite homovanillic acid in the cerebrospinal fluid. There are no disease modifying therapies for this life-limiting disorder. The aims of this study were to evaluate the clinical disease spectrum and develop a novel gene therapy approach for DTDS. Methods Patients aged 1–36 years with childhood-onset dystonia-parkinsonism and suggestive neurotransmitter profile had SLC6A3 sequenced. In-vitro functional studies were undertaken for identified missense mutations. We specifically phenotyped DAT knockout (–/–) mice motor behaviour as a model of DTDS and developed a preclinical viral gene therapy construct. We evaluated effects of intracranial delivery of DAT gene therapy in neonatal DAT–/– mice as a proof of concept study. Findings We identified ten new patients harbouring seven novel missense mutations, and found a novel atypical phenotype of juvenile parkinsonism. In-vitro functional characterisation revealed multifactorial disease mechanisms, including abnormal DAT trafficking, glycosylation, and impaired substrate recognition and uptake function. The DAT–/– mouse clearly recapitulated many features of human disease, including reduced survival, early hyperkinesia with later parkinsonism, raised homovanillic acid concentrations, and neurodegeneration. We have evaluated viral gene therapy approaches to target dopaminergic neurons and subsequently delivered DAT via adeno-associated virus type 9 to neonatal DAT–/– mice, with improved survival rates and motor phenotype. Interpretation We report an expanding disease spectrum in DTDS, in which the clinical presentation mimics both cerebral palsy and juvenile parkinsonism. Genotype–phenotype correlation is evident, with in-vitro functional studies demonstrating greater residual DAT function in later-onset milder forms of disease. The preclinical study of viral gene therapy in neonatal mice is promising and will facilitate the longer term aim towards clinical translation for this untreatable disorder. Funding Medical Research Council Clinical Research Training Fellowship, Great Ormond Street Hospital Children's Charity.
ISSN:0140-6736
1474-547X
DOI:10.1016/S0140-6736(16)00464-5