Journal article
A combined cell and gene therapy approach for homotopic reconstruction of midbrain dopamine pathways using human pluripotent stem cells
N Moriarty, CW Gantner, CPJ Hunt, CM Ermine, S Frausin, S Viventi, DA Ovchinnikov, D Kirik, CL Parish, LH Thompson
Cell Stem Cell | Published : 2022
Abstract
Midbrain dopamine (mDA) neurons can be replaced in patients with Parkinson's disease (PD) in order to provide long-term improvement in motor functions. The limited capacity for long-distance axonal growth in the adult brain means that cells are transplanted ectopically, into the striatal target. As a consequence, several mDA pathways are not re-instated, which may underlie the incomplete restoration of motor function in patients. Here, we show that viral delivery of GDNF to the striatum, in conjunction with homotopic transplantation of human pluripotent stem-cell-derived mDA neurons, recapitulates brain-wide mDA target innervation. The grafts provided re-instatement of striatal dopamine leve..
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Funding Acknowledgements
The authors thank Brianna Xuereb and Mong Tien for expert technical assis-tance in the surgical, behavioral, tissue preparation, and immunohistochem-ical procedures and Bjod rn Anzelius for production of the AAV-GDNF virus. C.L.P. was supported by a National Health and Medical Research Council Australia (NHMRC) Senior Research Fellowship. C.W.G. was supported by an Australian Postgraduate Award. The work was supported by the Australian Medical Research Future Fund (#1202181 to L.H.T.) , NHMRC Australia project grants (#1130734 to L.H.T. and #1102704 to C.L.P.) , the Swedish Research Council (2012-2586 to D.K.) , and the Aligning Science Across Parkinson's initiative. This work was also made possible through philanthropic funding from the JEM Foundation and the vision of John Ebsary to support technical innovation in medical research. The Florey Institute of Neuroscience and Mental Health acknowledges the strong support from the Victorian Government and in particular the funding from the Operational Infrastructure Support Grant.