Gene therapy restores dopamine transporter expression and ameliorates pathology in iPSC and mouse models of infantile parkinsonism
Joanne Ng, Serena Barral, Carmen De La Fuente Barrigon, Gabriele Lignani, Fatma A. Erdem, Rebecca L. Wallings, Riccardo Privolizzi, Giada Rossignoli, Haya Alrashidi, Sonja Heasman, Esther Meyer, Adeline Ngoh, Simon Pope, Rajvinder Karda, Dany Perocheau, Julien Baruteau, Natalie Suff, Juan Antinao Díaz, Stéphanie Schorge, Jane Vowles, Lucy Marshall, Sally A. Cowley, Sonja Sučić, Michael Freissmuth, John R. Counsell, Richard Wade‐Martins, Simon Heales, Ahad A. Rahim, Maximilien Bencze, Simon N. Waddington, Manju A. Kurian
Abstract
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.