Gene therapy for an inherited childhood parkinsonism - dopamine transporter deficiency syndrome

Dopamine transporter deficiency syndrome is caused by biallelic loss-of-function mutations in SLC6A3, encoding the dopamine transporter. 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. To progress toward clinical translation, we used the knockout mouse model of this disease, that recapitulates human disease, exhibiting parkinsonism features, including tremor, bradykinesia, and premature death. Stereotactic delivery of AAV2.SLC6A3 gene therapy targeted to the midbrain of adult knockout mice rescued both motor phenotype and neurodegeneration, suggesting that targeted AAV gene therapy might be effective for patients with dopamine transporter deficiency syndrome.