title: Human Mesenchymal Stem Cells Genetically Engineered to Overexpress Brain-derived Neurotrophic Factor Improve Outcomes in Huntington's Disease Mouse Models.
abstract: Huntington's disease (HD) is a fatal degenerative autosomal dominant neuropsychiatric disease that causes neuronal death and is characterized by progressive striatal and then widespread brain atrophy. Brain-derived neurotrophic factor (BDNF) is a lead candidate for the treatment of HD, as it has been shown to prevent cell death and to stimulate the growth and migration of new neurons in the brain in transgenic mouse models. BDNF levels are reduced in HD postmortem human brain. Previous studies have shown efficacy of mesenchymal stem/stromal cells (MSC)/BDNF using murine MSCs, and the present study used human MSCs to advance the therapeutic potential of the MSC/BDNF platform for clinical application. Double-blinded studies were performed to examine the effects of intrastriatally transplanted human MSC/BDNF on disease progression in two strains of immune-suppressed HD transgenic mice: YAC128 and R6/2. MSC/BDNF treatment decreased striatal atrophy in YAC128 mice. MSC/BDNF treatment also significantly reduced anxiety as measured in the open-field assay. Both MSC and MSC/BDNF treatments induced a significant increase in neurogenesis-like activity in R6/2 mice. MSC/BDNF treatment also increased the mean lifespan of the R6/2 mice. Our genetically modified MSC/BDNF cells set a precedent for stem cell-based neurotherapeutics and could potentially be modified for other neurodegenerative disorders such as amyotrophic lateral sclerosis, Alzheimer's disease, and some forms of Parkinson's disease. These cells provide a platform delivery system for future studies involving corrective gene-editing strategies.
authors.affiliation: Stem Cell Program and Institute for Regenerative Cures, University of California Davis Health System, Sacramento, California, USA.
authors.forename: Kari
authors.initials: K
authors.lastname: Pollock
authors.affiliation: Stem Cell Program and Institute for Regenerative Cures, University of California Davis Health System, Sacramento, California, USA.
authors.forename: Heather
authors.initials: H
authors.lastname: Dahlenburg
authors.affiliation: Stem Cell Program and Institute for Regenerative Cures, University of California Davis Health System, Sacramento, California, USA.
authors.forename: Haley
authors.initials: H
authors.lastname: Nelson
authors.affiliation: Stem Cell Program and Institute for Regenerative Cures, University of California Davis Health System, Sacramento, California, USA.
authors.forename: Kyle D
authors.initials: KD
authors.lastname: Fink
authors.affiliation: Stem Cell Program and Institute for Regenerative Cures, University of California Davis Health System, Sacramento, California, USA.
authors.forename: Whitney
authors.initials: W
authors.lastname: Cary
authors.affiliation: Stem Cell Program and Institute for Regenerative Cures, University of California Davis Health System, Sacramento, California, USA.
authors.forename: Kyle
authors.initials: K
authors.lastname: Hendrix
authors.affiliation: Stem Cell Program and Institute for Regenerative Cures, University of California Davis Health System, Sacramento, California, USA.
authors.forename: Geralyn
authors.initials: G
authors.lastname: Annett
authors.affiliation: Stem Cell Program and Institute for Regenerative Cures, University of California Davis Health System, Sacramento, California, USA.
authors.forename: Audrey
authors.initials: A
authors.lastname: Torrest
authors.affiliation: Stem Cell Program and Institute for Regenerative Cures, University of California Davis Health System, Sacramento, California, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Deng
authors.affiliation: Stem Cell Program and Institute for Regenerative Cures, University of California Davis Health System, Sacramento, California, USA.
authors.forename: Joshua
authors.initials: J
authors.lastname: Gutierrez
authors.affiliation: Stem Cell Program and Institute for Regenerative Cures, University of California Davis Health System, Sacramento, California, USA.
authors.forename: Catherine
authors.initials: C
authors.lastname: Nacey
authors.affiliation: Stem Cell Program and Institute for Regenerative Cures, University of California Davis Health System, Sacramento, California, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: Pepper
authors.affiliation: Stem Cell Program and Institute for Regenerative Cures, University of California Davis Health System, Sacramento, California, USA.
authors.forename: Stefanos
authors.initials: S
authors.lastname: Kalomoiris
authors.affiliation: Stem Cell Program and Institute for Regenerative Cures, University of California Davis Health System, Sacramento, California, USA.
authors.forename: Johnathon
authors.initials: J
authors.lastname: D Anderson
authors.affiliation: Stem Cell Program and Institute for Regenerative Cures, University of California Davis Health System, Sacramento, California, USA.
authors.forename: Jeannine
authors.initials: J
authors.lastname: McGee
authors.affiliation: Stem Cell Program and Institute for Regenerative Cures, University of California Davis Health System, Sacramento, California, USA.
authors.forename: William
authors.initials: W
authors.lastname: Gruenloh
authors.affiliation: Stem Cell Program and Institute for Regenerative Cures, University of California Davis Health System, Sacramento, California, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Fury
authors.affiliation: Stem Cell Program and Institute for Regenerative Cures, University of California Davis Health System, Sacramento, California, USA.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Bauer
authors.affiliation: Department of Neurology, University of California Davis Health System, Sacramento, California, USA.
authors.forename: Alexandria
authors.initials: A
authors.lastname: Duffy
authors.affiliation: Department of Neurology, University of California Davis Health System, Sacramento, California, USA.
authors.forename: Theresa
authors.initials: T
authors.lastname: Tempkin
authors.affiliation: Department of Neurology, University of California Davis Health System, Sacramento, California, USA.
authors.forename: Vicki
authors.initials: V
authors.lastname: Wheelock
authors.affiliation: Stem Cell Program and Institute for Regenerative Cures, University of California Davis Health System, Sacramento, California, USA.
authors.forename: Jan A
authors.initials: JA
authors.lastname: Nolta