Human mesenchymal stem cells genetically engineered to overexpress brain-derived neurotrophic factor improve outcomes in huntington's disease mouse models

Kari Pollock, Heather Dahlenburg, Haley Nelson, Kyle D. Fink, Whitney Cary, Kyle Hendrix, Geralyn Annett, Audrey Torrest, Peter Deng, Joshua Gutierrez, Catherine Nacey, Karen Pepper, Stefanos Kalomoiris, Johnathon D. Anderson, Jeannine McGee, William Gruenloh, Brian Fury, Gerhard Bauer, Alexandria Duffy, Theresa TempkinVicki Wheelock, Jan A. Nolta

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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.

Original languageEnglish (US)
Pages (from-to)965-977
Number of pages13
JournalMolecular Therapy
Volume24
Issue number5
DOIs
StatePublished - May 1 2016

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ASJC Scopus subject areas

  • Molecular Biology
  • Molecular Medicine
  • Genetics
  • Drug Discovery
  • Pharmacology

Cite this

Pollock, K., Dahlenburg, H., Nelson, H., Fink, K. D., Cary, W., Hendrix, K., Annett, G., Torrest, A., Deng, P., Gutierrez, J., Nacey, C., Pepper, K., Kalomoiris, S., Anderson, J. D., McGee, J., Gruenloh, W., Fury, B., Bauer, G., Duffy, A., ... Nolta, J. A. (2016). Human mesenchymal stem cells genetically engineered to overexpress brain-derived neurotrophic factor improve outcomes in huntington's disease mouse models. Molecular Therapy, 24(5), 965-977. https://doi.org/10.1038/mt.2016.12