title: Human ESC-derived dopamine neurons show similar preclinical efficacy and potency to fetal neurons when grafted in a rat model of Parkinson's disease.
abstract: Considerable progress has been made in generating fully functional and transplantable dopamine neurons from human embryonic stem cells (hESCs). Before these cells can be used for cell replacement therapy in Parkinson's disease (PD), it is important to verify their functional properties and efficacy in animal models. Here we provide a comprehensive preclinical assessment of hESC-derived midbrain dopamine neurons in a rat model of PD. We show long-term survival and functionality using clinically relevant MRI and PET imaging techniques and demonstrate efficacy in restoration of motor function with a potency comparable to that seen with human fetal dopamine neurons. Furthermore, we show that hESC-derived dopamine neurons can project sufficiently long distances for use in humans, fully regenerate midbrain-to-forebrain projections, and innervate correct target structures. This provides strong preclinical support for clinical translation of hESC-derived dopamine neurons using approaches similar to those established with fetal cells for the treatment of Parkinson's disease.
authors.affiliation: Developmental and Regenerative Neurobiology, Department of Experimental Medical Science, Wallenberg Neuroscience Center, Lund University, 22184 Lund, Sweden; Lund Stem Cell Center, Lund University, 22184 Lund, Sweden. Electronic address: shane.grealish@med.lu.se.
authors.forename: Shane
authors.initials: S
authors.lastname: Grealish
authors.affiliation: Molecular Imaging Research Centre (MIRCen), Commissariat à l'Energie Atomique (CEA), 92264 Fontenay-aux-Roses, France.
authors.forename: Elsa
authors.initials: E
authors.lastname: Diguet
authors.affiliation: Developmental and Regenerative Neurobiology, Department of Experimental Medical Science, Wallenberg Neuroscience Center, Lund University, 22184 Lund, Sweden; Lund Stem Cell Center, Lund University, 22184 Lund, Sweden.
authors.forename: Agnete
authors.initials: A
authors.lastname: Kirkeby
authors.affiliation: Developmental and Regenerative Neurobiology, Department of Experimental Medical Science, Wallenberg Neuroscience Center, Lund University, 22184 Lund, Sweden.
authors.forename: Bengt
authors.initials: B
authors.lastname: Mattsson
authors.affiliation: Developmental and Regenerative Neurobiology, Department of Experimental Medical Science, Wallenberg Neuroscience Center, Lund University, 22184 Lund, Sweden; Lund Stem Cell Center, Lund University, 22184 Lund, Sweden.
authors.forename: Andreas
authors.initials: A
authors.lastname: Heuer
authors.affiliation: Molecular Imaging Research Centre (MIRCen), Commissariat à l'Energie Atomique (CEA), 92264 Fontenay-aux-Roses, France.
authors.forename: Yann
authors.initials: Y
authors.lastname: Bramoulle
authors.affiliation: Molecular Imaging Research Centre (MIRCen), Commissariat à l'Energie Atomique (CEA), 92264 Fontenay-aux-Roses, France.
authors.forename: Nadja
authors.initials: N
authors.lastname: Van Camp
authors.affiliation: Inserm U861, I-Stem, AFM, 91030 Evry Cedex, France; UEVE U861, I-Stem, AFM, 91030 Evry Cedex, France.
authors.forename: Anselme L
authors.initials: AL
authors.lastname: Perrier
authors.affiliation: Molecular Imaging Research Centre (MIRCen), Commissariat à l'Energie Atomique (CEA), 92264 Fontenay-aux-Roses, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Hantraye
authors.affiliation: Developmental and Regenerative Neurobiology, Department of Experimental Medical Science, Wallenberg Neuroscience Center, Lund University, 22184 Lund, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Björklund
authors.affiliation: Developmental and Regenerative Neurobiology, Department of Experimental Medical Science, Wallenberg Neuroscience Center, Lund University, 22184 Lund, Sweden; Lund Stem Cell Center, Lund University, 22184 Lund, Sweden. Electronic address: malin.parmar@med.lu.se.
authors.forename: Malin
authors.initials: M
authors.lastname: Parmar
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism; D002470:Cell Survival; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000166:cytology* / Q000637:transplantation*; D053595:Embryonic Stem Cells / Q000166:cytology*; D005333:Fetus / Q000166:cytology*; D006801:Humans; D008297:Male; D008636:Mesencephalon / Q000196:embryology; D017072:Neostriatum / Q000473:pathology; D051857:Otx Transcription Factors / Q000378:metabolism; D010300:Parkinson Disease / Q000473:pathology / Q000628:therapy*; D011923:Rats, Nude; D013378:Substantia Nigra / Q000473:pathology; D009435:Synaptic Transmission; D013997:Time Factors
chemical_list: C497659:OTX2 protein, human; D051857:Otx Transcription Factors