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A combined cell and gene therapy approach

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    A combined cell and gene therapy approach

    A combined cell and gene therapy approach for homotopic reconstruction of midbrain dopamine pathways using human pluripotent stem cells

    Niamh Moriarty 1, Carlos W Gantner 1, Cameron P J Hunt 1, Charlotte M Ermine 1, Stefano Frausin 1, Serena Viventi 1, Dmitry A Ovchinnikov 1, Deniz Kirik 2, Clare L Parish 3, Lachlan H Thompson 4
    Affiliations expandAbstract

    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 levels and correction of motor function and also connectivity with additional mDA target nuclei not well innervated by ectopic grafts. These results demonstrate the remarkable capacity for achieving functional and anatomically precise reconstruction of long-distance circuitry in the adult brain by matching appropriate growth-factor signaling to grafting of specific cell types.

    Keywords: GDNF; PITX3; Parkinson’s disease; axon growth; cell therapy; neural transplantation; neurotrophic; regeneration; retrograde tracing; substantia nigra.
    “As the cast of villains in SCI is vast and collaborative, so too must be the chorus of hero's that rise to meet them” Ramer et al 2005