title: Neural Stem Cells Derived from Human Parthenogenetic Stem Cells Engraft and Promote Recovery in a Nonhuman Primate Model of Parkinson's Disease.
abstract: Cell therapy has attracted considerable interest as a promising therapeutic alternative for patients with Parkinson's disease (PD). Clinical studies have shown that grafted fetal neural tissue can achieve considerable biochemical and clinical improvements in PD. However, the source of fetal tissue grafts is limited and ethically controversial. Human parthenogenetic stem cells offer a good alternative because they are derived from unfertilized oocytes without destroying potentially viable human embryos and can be used to generate an unlimited supply of neural cells for transplantation. We have previously reported that human parthenogenetic stem cell-derived neural stem cells (hpNSCs) successfully engraft, survive long term, and increase brain dopamine (DA) levels in rodent and nonhuman primate models of PD. Here we report the results of a 12-month transplantation study of hpNSCs in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned African green monkeys with moderate to severe clinical parkinsonian symptoms. The hpNSCs manufactured under current good manufacturing practice (cGMP) conditions were injected bilaterally into the striatum and substantia nigra of immunosuppressed monkeys. Transplantation of hpNSCs was safe and well tolerated by the animals with no dyskinesia, tumors, ectopic tissue formation, or other test article-related serious adverse events. We observed that hpNSCs promoted behavioral recovery; increased striatal DA concentration, fiber innervation, and number of dopaminergic neurons; and induced the expression of genes and pathways downregulated in PD compared to vehicle control animals. These results provide further evidence for the clinical translation of hpNSCs and support the approval of the world's first pluripotent stem cell-based phase I/IIa study for the treatment of PD (Clinical Trial Identifier NCT02452723).
authors.affiliation: International Stem Cell Corporation, Carlsbad, CA, USA.
authors.forename: Rodolfo
authors.initials: R
authors.lastname: Gonzalez
authors.affiliation: International Stem Cell Corporation, Carlsbad, CA, USA.
authors.forename: Ibon
authors.initials: I
authors.lastname: Garitaonandia
authors.affiliation: International Stem Cell Corporation, Carlsbad, CA, USA.
authors.forename: Maxim
authors.initials: M
authors.lastname: Poustovoitov
authors.affiliation: International Stem Cell Corporation, Carlsbad, CA, USA.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Abramihina
authors.affiliation: Axion Research Foundation, Hamden, CT, USA.
authors.forename: Caleb
authors.initials: C
authors.lastname: McEntire
authors.affiliation: Axion Research Foundation, Hamden, CT, USA.
authors.forename: Ben
authors.initials: B
authors.lastname: Culp
authors.affiliation: Axion Research Foundation, Hamden, CT, USA.
authors.forename: Jordan
authors.initials: J
authors.lastname: Attwood
authors.affiliation: International Stem Cell Corporation, Carlsbad, CA, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Noskov
authors.affiliation: International Stem Cell Corporation, Carlsbad, CA, USA.
authors.forename: Trudy
authors.initials: T
authors.lastname: Christiansen-Weber
authors.affiliation: Department of Reproductive Medicine, University of California San Diego, La Jolla, CA, USA.
authors.forename: Marwa
authors.initials: M
authors.lastname: Khater
authors.affiliation: Department of Reproductive Medicine, University of California San Diego, La Jolla, CA, USA.
authors.forename: Sergio
authors.initials: S
authors.lastname: Mora-Castilla
authors.affiliation: Department of Reproductive Medicine, University of California San Diego, La Jolla, CA, USA.
authors.forename: Cuong
authors.initials: C
authors.lastname: To
authors.affiliation: Stem Cell Research Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Crain
authors.affiliation: International Stem Cell Corporation, Carlsbad, CA, USA.
authors.forename: Glenn
authors.initials: G
authors.lastname: Sherman
authors.affiliation: International Stem Cell Corporation, Carlsbad, CA, USA.
authors.forename: Andrey
authors.initials: A
authors.lastname: Semechkin
authors.affiliation: Department of Reproductive Medicine, University of California San Diego, La Jolla, CA, USA.
authors.forename: Louise C
authors.initials: LC
authors.lastname: Laurent
authors.affiliation: Department of Psychiatry and Neurosurgery, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: John D
authors.initials: JD
authors.lastname: Elsworth
authors.affiliation: Department of Neurology, Pediatrics and Neuroscience, University of Colorado School of Medicine, Aurora, CO, USA.
authors.forename: John
authors.initials: J
authors.lastname: Sladek
authors.affiliation: Stem Cell Research Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
authors.forename: Evan Y
authors.initials: EY
authors.lastname: Snyder
authors.affiliation: Axion Research Foundation, Hamden, CT, USA.|Department of Psychiatry and Neurosurgery, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: D Eugene
authors.initials: DE
authors.lastname: Redmond
authors.affiliation: International Stem Cell Corporation, Carlsbad, CA, USA.
authors.forename: Russell A
authors.initials: RA
authors.lastname: Kern
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D016000:Cluster Analysis; D003342:Corpus Striatum / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D006801:Humans; D007150:Immunohistochemistry; D059785:Karyotype; D020267:MPTP Poisoning / Q000139:chemically induced / Q000473:pathology / Q000628:therapy*; D008297:Male; D058953:Neural Stem Cells / Q000166:cytology / Q000637:transplantation*; D010312:Parthenogenesis; D020127:Recovery of Function / Q000502:physiology*
chemical_list: D004298:Dopamine
keywords: Cell therapy; Human parthenogenetic stem cells (hpSCs); Neural stem cells (NSCs); Parkinson's disease (PD); Pluripotent stem cells