Research ArticleParkinson’s Disease

Gene therapy restores dopamine transporter expression and ameliorates pathology in iPSC and mouse models of infantile parkinsonism

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Science Translational Medicine  19 May 2021:
Vol. 13, Issue 594, eaaw1564
DOI: 10.1126/scitranslmed.aaw1564

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Delivering a transporter

Dopamine transporter deficiency syndrome (DTDS) is a rare neurodegenerative disease caused by biallelic loss-of-function mutations in SLC6A3, the gene encoding the dopamine transporter (DAT). There is no effective treatment for this disease and the pathophysiology is still unclear; patients develop infantile parkinsonism that often leads to premature death. Here, Ng et al. developed a gene therapy for DTDS using patient-derived induced pluripotent stem cell (iPSC) and a mouse model. Delivery of human SLC6A3 improved DAT activity and reduced neurodegeneration in vitro in iPSC-derived neurons. In vivo, injection of SLC6A3 in the midbrain of adult DTDS mice using an adeno-associated virus vector had therapeutic effects, suggesting that the approach might be effective in patients.


Most inherited neurodegenerative disorders are incurable, and often only palliative treatment is available. Precision medicine has great potential to address this unmet clinical need. We explored this paradigm in dopamine transporter deficiency syndrome (DTDS), caused by biallelic loss-of-function mutations in SLC6A3, encoding the dopamine transporter (DAT). Patients present with early infantile hyperkinesia, severe progressive childhood parkinsonism, and raised cerebrospinal fluid dopamine metabolites. The absence of effective treatments and relentless disease course frequently leads to death in childhood. Using patient-derived induced pluripotent stem cells (iPSCs), we generated a midbrain dopaminergic (mDA) neuron model of DTDS that exhibited marked impairment of DAT activity, apoptotic neurodegeneration associated with TNFα-mediated inflammation, and dopamine toxicity. Partial restoration of DAT activity by the pharmacochaperone pifithrin-μ was mutation-specific. In contrast, lentiviral gene transfer of wild-type human SLC6A3 complementary DNA restored DAT activity and prevented neurodegeneration in all patient-derived mDA lines. To progress toward clinical translation, we used the knockout mouse model of DTDS that recapitulates human disease, exhibiting parkinsonism features, including tremor, bradykinesia, and premature death. Neonatal intracerebroventricular injection of human SLC6A3 using an adeno-associated virus (AAV) vector provided neuronal expression of human DAT, which ameliorated motor phenotype, life span, and neuronal survival in the substantia nigra and striatum, although off-target neurotoxic effects were seen at higher dosage. These were avoided with stereotactic delivery of AAV2.SLC6A3 gene therapy targeted to the midbrain of adult knockout mice, which rescued both motor phenotype and neurodegeneration, suggesting that targeted AAV gene therapy might be effective for patients with DTDS.

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