Mol Neurobiol (2012) 45:87–98 DOI 10.1007/s12035-011-8219-8 Genetically Engineered Mesenchymal Stem Cells as a Proposed Therapeutic for Huntington’s Disease Scott D. Olson & Kari Pollock & Amal Kambal & Whitney Cary & Gaela-Marie Mitchell & Jeremy Tempkin & Heather Stewart & Jeannine McGee & Gerhard Bauer & Hyun Sook Kim & Teresa Tempkin & Vicki Wheelock & Geralyn Annett & Gary Dunbar & Jan A. Nolta Received: 21 August 2011 / Accepted: 9 November 2011 / Published online: 9 December 2011 # The Author(s) 2011. This article is published with open access at Springerlink.com Abstract There is much interest in the use of mesenchymal stem cells/marrow stromal cells (MSC) to treat neurode- generative disorders, in particular those that are fatal and difficult to treat, such as Huntington’s disease. MSC present a promising tool for cell therapy and are currently being tested in FDA-approved phase I–III clinical trials for many disorders. In preclinical studies of neurodegenerative dis- orders, MSC have demonstrated efficacy, when used as delivery vehicles for neural growth factors. A number of investigators have examined the potential benefits of innate MSC-secreted trophic support and augmented growth factors to support injured neurons. These include over- expression of brain-derived neurotrophic factor and glial- derived neurotrophic factor, using genetically engineered MSC as a vehicle to deliver the cytokines directly into the microenvironment. Proposed regenerative approaches to S. D. Olson : K. Pollock : A. Kambal : W. Cary : G.-M. Mitchell : J. Tempkin : H. Stewart : J. McGee : G. Bauer : H. S. Kim : G. Annett : J. A. Nolta (*) Stem Cell Program and Institute for Regenerative Cures, University of California Davis Health Systems, 2921 Stockton Blvd., Room 1300, Sacramento, CA 95817, USA e-mail: Jan.nolta@ucdmc.ucdavis.edu URL: http://www.ucdmc.ucdavis.edu/stemcellresearch T. Tempkin : V. Wheelock Department of Neurology, University of California Davis Health Systems, Sacramento, CA, USA H. S. Kim Department of Neurology, CHA University School of Medicine, Bundang, South Korea G. Dunbar Department of Psychology, Central Michigan University, Mount Pleasant, MI, USA neurological diseases using MSC include cell therapies in which cells are delivered via intracerebral or intrathecal injection. Upon transplantation, MSC in the brain promote endogenous neuronal growth, encourage synaptic connec- tion from damaged neurons, decrease apoptosis, reduce levels of free radicals, and regulate inflammation. These abilities are primarily modulated through paracrine actions. Clinical trials for MSC injection into the central nervous system to treat amyotrophic lateral sclerosis, traumatic brain injury, and stroke are currently ongoing. The current data in support of applying MSC-based cellular therapies to the treatment of Huntington’s disease is discussed. Keywords Human mesenchymal stem cells . Neurite outgrowth . Neurodegenerative diseases . Hypoxia . Tissue repair . Huntington’s disease . Clinical trials . BDNF Abbreviations ALS Amyotrophic lateral sclerosis BDNF Brain-derived neurotrophic factor CSF Cerebrospinal fluid FGF-2 Fibroblast growth factor-2 GDNF Glial-derived neurotrophic factor GMP Good Manufacturing Practice GLP Good laboratory practice HD Huntington’s disease HGF Hepatocyte growth factor hESC Human embryonic stem cells HSCT Hematopoietic stem cell transplantation HTT Huntingtin gene, mRNA, or protein IGF-1 Insulin-like growth factor-I MSC Mesenchymal stem cells NSC Neural stem cells OEC Olfactory ensheathing cells