Developing stem cell therapies for juvenile and adult-onset Huntington's disease

Kyle D Fink, Peter Deng, Audrey Torrest, Heather Stewart, Kari Pollock, William Gruenloh, Geralyn Annett, Teresa Tempkin, Vicki Wheelock, Jan A Nolta, Kyle D Fink, Peter Deng, Audrey Torrest, Heather Stewart, Kari Pollock, William Gruenloh, Geralyn Annett, Teresa Tempkin, Vicki Wheelock, Jan A Nolta

Abstract

Stem cell therapies have been explored as a new avenue for the treatment of neurologic disease and damage within the CNS in part due to their native ability to mimic repair mechanisms in the brain. Mesenchymal stem cells have been of particular clinical interest due to their ability to release beneficial neurotrophic factors and their ability to foster a neuroprotective microenviroment. While early stem cell transplantation therapies have been fraught with technical and political concerns as well as limited clinical benefits, mesenchymal stem cell therapies have been shown to be clinically beneficial and derivable from nonembryonic, adult sources. The focus of this review will be on emerging and extant stem cell therapies for juvenile and adult-onset Huntington's disease.

Keywords: Huntington's disease; regenerative medicine; stem cell; transplantation.

Conflict of interest statement

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

References

    1. Dutta S, Singh G, Sreejith S et al. Cell therapy: the final frontier for treatment of neurological diseases. CNS Neurosci. Ther 19(1), 5–11 (2013).
    1. Barker RA. Stem cells and neurodegenerative diseases: where is it all going? Regen. Med 7(6 Suppl), 26–31 (2012).
    1. Karussis D, Petrou P, Kassis I. Clinical experience with stem cells and other cell therapies in neurological diseases. J. Neurol. Sci 324(1–2), 1–9 (2013).
    1. Bachoud-Lévi A-C, Gaura V, Brugières P et al. Effect of fetal neural transplants in patients with Huntington’s disease 6 years after surgery: a long-term follow-up study. Lancet Neurol. 5(4), 303–309 (2006).
    1. Cicchetti F, Saporta S, Hauser RA et al. Neural transplants in patients with Huntington’s disease undergo disease-like neuronal degeneration. Proc. Natl Acad. Sci. USA 106(30), 12483–12488 (2009).
    1. Keene CD, Chang RC, Leverenz JB et al. A patient with Huntington’s disease and long-surviving fetal neural transplants that developed mass lesions. Acta Neuropathol. (Berl.). 117(3), 329–338 (2009).
    1. Venkataramana NK, Kumar SKV, Balaraju S et al. Open-labeled study of unilateral autologous bone-marrow-derived mesenchymal stem cell transplantation in Parkinson’s disease. Transl. Res. J. Lab. Clin. Med 155(2), 62–70 (2010).
    1. Boncoraglio GB, Bersano A, Candelise L, Reynolds BA, Parati EA. Stem cell transplantation for ischemic stroke. Cochrane Database Syst. Rev. Online (9), CD007231 (2010).
    1. Lee JS, Hong JM, Moon GJ et al. A long-term follow-up study of intravenous autologous mesenchymal stem cell transplantation in patients with ischemic stroke. Stem Cells Dayt. Ohio 28(6), 1099–1106 (2010).
    1. Lee Y-H, Choi KV, Moon JH et al. Safety and feasibility of countering neurological impairment by intravenous administration of autologous cord blood in cerebral palsy. J. Transl. Med 10, 10 (2012).
    1. Madhavan L, Collier TJ. A synergistic approach for neural repair: cell transplantation and induction of endogenous precursor cell activity. Neuropharmacology 58(6), 835–844 (2010).
    1. The Huntington’s Collaborative Research Group. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes The Huntington’s Disease Collaborative Research Group; Cell 72(6), 971–983 (1993).

    1. Shoulson I, Young AB. Milestones in huntington disease. Mov. Disord 26(6), 1127–1133 (2011).

      • Excellent review of the major progress in the treatment, drug development, therapeutic targets and etiology of Hungtington’s disease (HD).

    1. Ribaï P, Nguyen K, Hahn-Barma V et al. Psychiatric and cognitive difficulties as indicators of juvenile huntington disease onset in 29 patients. Arch. Neurol 64(6), 813–819 (2007).
    1. Gonzalez-Alegre P, Afifi AK. Clinical characteristics of childhood-onset (juvenile) Huntington disease: report of 12 patients and review of the literature. J. Child Neurol 21(3), 223–229 (2006).
    1. Estrada Sánchez AM, Mejía-Toiber J, Massieu L. Excitotoxic neuronal death and the pathogenesis of Huntington’s disease. Arch. Med. Res 39(3), 265–276 (2008).
    1. Nance MA, Mathias-Hagen V, Breningstall G, Wick MJ, McGlennen RC. Analysis of a very large trinucleotide repeat in a patient with juvenile Huntington’s disease. Neurology 52(2), 392–394 (1999).
    1. Biglan K, Shoulson I. Juvenile-onset huntington disease: a matter of perspective. Arch. Neurol 64(6), 783–784 (2007).
    1. Klempír J, Klempírová O, Stochl J, Spacková N, Roth J. The relationship between impairment of voluntary movements and cognitive impairment in Huntington’s disease. J. Neurol 256(10), 1629–1633 (2009).
    1. Ross CA, Aylward EH, Wild EJ et al. Huntington disease: natural history, biomarkers and prospects for therapeutics. Nat. Rev. Neurol 10(4), 204–216 (2014).
    1. Douglas I, Evans S, Rawlins MD, Smeeth L, Tabrizi SJ, Wexler NS. Juvenile Huntington’s disease: a population-based study using the General Practice Research Database. BMJ Open doi:10.1136/bmjopen-2012-002085 (2013) (Epub ahead of print).
    1. Stout JC, Weaver M, Solomon AC et al. Are cognitive changes progressive in prediagnostic HD? Cogn. Behav. Neurol 20(4), 212–218 (2007).

    1. Aylward EH, Rosenblatt A, Field K et al. Caudate volume as an outcome measure in clinical trials for Huntington’s disease: a pilot study. Brain Res. Bull 62(2), 137–141 (2003).

      •One of the first to establish robust clinical measurements to track the progression of HD. The results from this study help to design clinical trials aimed at slowing or at tenuating disease progression.

    1. Tabrizi SJ, Langbehn DR, Leavitt BR et al. Biological and clinical manifestations of Huntington’s disease in the longitudinal TRACK-HD study: cross-sectional analysis of baseline data. Lancet Neurol. 8(9), 791–801 (2009).

    1. Southwell AL, Ko J, Patterson PH. Intrabody gene therapy ameliorates motor, cognitive, and neuropathological symptoms in multiple mouse models of Huntington’s disease. J. Neurosci 29(43), 13589–13602 (2009).

      •One of the first to report significant in vivo data in transgenic mouse models of HD supporting the hypothesis that if mutant huntingtin was reduced the behavioral and neuropathological deficits would also be reduced.

    1. Wang N, Gray M, Lu X-H et al. Neuronal targets for reducing mutant huntingtin expression to ameliorate disease in a mouse model of Huntington’s disease. Nat. Med 20(5), 536–541 (2014).
    1. Mielcarek M, Inuabasi L, Bondulich MK et al. Dysfunction of the CNS-heart axis in mouse models of Huntington’s disease. PLoS Genet. 10(8), e1004550 (2014).
    1. Buonincontri G, Wood NI, Puttick SG et al. Right ventricular dysfunction in the R6/2 transgenic mouse model of Huntington’s disease is unmasked by dobutamine. J. Huntingt. Dis 3(1), 25–32 (2014).
    1. Mihm MJ, Amann DM, Schanbacher BL, Altschuld RA, Bauer JA, Hoyt KR. Cardiac dysfunction in the R6/2 mouse model of Huntington’s disease. Neurobiol. Dis 25(2), 297–308 (2007).
    1. Zielonka D, Piotrowska I, Marcinkowski JT, Mielcarek M. Skeletal muscle pathology in Huntington’s disease. Front. Physiol 5, 5 (2014).
    1. Sari Y. Potential drugs and methods for preventing or delaying the progression of Huntington’s disease. Recent Patents CNS Drug Discov. 6(2), 80–90 (2011).
    1. Venuto CS, McGarry A, Ma Q, Kieburtz K. Pharmacologic approaches to the treatment of Huntington’s disease. Mov. Disord 27(1), 31–41 (2012).
    1. Lescaudron L, Unni D, Dunbar GL. Autologous adult bone marrow stem cell transplantation in an animal model of hunrington’s disease: behavioral and morphological outcomes. Int. J. Neurosci 113(7), 945–956 (2003).
    1. Jiang Y, Lv H, Huang S, Tan H, Zhang Y, Li H. Bone marrow mesenchymal stem cells can improve the motor function of a Huntington’s disease rat model. Neurol. Res 33(3), 331–337 (2011).
    1. Rossignol J, Boyer C, Lévèque X et al. Mesenchymal stem cell transplantation and DMEM administration in a 3NP rat model of Huntington’s disease: morphological and behavioral outcomes. Behav. Brain Res 217(2), 369–378 (2011).

    1. Rossignol J, Fink K, Davis K et al. Transplants of adult mesenchymal and neural stem cells provide neuroprotection and behavioral sparing in a transgenic rat model of Huntington’s disease. Stem Cells Dayt. Ohio 32(2), 500–509 (2013).

      •Provided evidence for the use of mesenchymal stem cells to both modulate the host microenvironment to increase survival of normally rejected transplanted cells and to provide functional and histological benefits by themselves.

    1. Sadan O, Shemesh N, Barzilay R et al. Migration of neurotrophic factors-secreting mesenchymal stem cells toward a quinolinic acid lesion as viewed by magnetic resonance imaging. Stem Cells Dayt. Ohio 26(10), 2542–2551 (2008).
    1. Serrano Sánchez T, Alberti Amador E, Lorigados Pedre L, Blanco Lezcano L, Diaz Armesto I, Bergado JA. BDNF in quinolinic acid lesioned rats after bone marrow cells transplant. Neurosci. Lett 559, 147–151 (2014).

    1. Dey ND, Bombard MC, Roland BP et al. Genetically engineered mesenchymal stem cells reduce behavioral deficits in the YAC 128 mouse model of Huntington’s disease. Behav. Brain Res 214(2), 193–200 (2010).

      ••A proof-of-concept study that demonstrated the role of BDNF released from mesenchymal stem cells to provide significant recovery or prevention of deficits in a transgenic mouse model of HD.

    1. Rossignol J, Fink KD, Crane AT et al. Reductions in behavioral deficits and neuropathology in the R6/2 mouse model of Huntington’s disease following transplantation of bone-marrow-derived mesenchymal stem cells is dependent on passage number. Stem Cell Res. Ther doi:10.1186/scrt545 (2015) (Epub ahead of print).
    1. Fink KD, Rossignol J, Crane AT et al. Transplantation of umbilical cord-derived mesenchymal stem cells into the striata of R6/2 mice: behavioral and neuropathological analysis. Stem Cell Res. Ther 4(5), 130 (2013).
    1. Hosseini M, Moghadas M, Edalatmanesh MA, Hashemzadeh MR. Xenotransplantation of human adipose derived mesenchymal stem cells in a rodent model of Huntington’s disease: motor and non-motor outcomes. Neurol. Res 37(4), 309–319 (2015).
    1. Im W, Lee S-T, Park JE et al. Transplantation of patient-derived adipose stem cells in YAC128 Huntington’s disease transgenic mice. PLoS Curr. 2 (2010).
    1. Lee S-T, Chu K, Jung K-H et al. Slowed progression in models of Huntington disease by adipose stem cell transplantation. Ann. Neurol 66(5), 671–681 (2009).

    1. Lin Y-T, Chern Y, Shen C-KJ et al. Human mesenchymal stem cells prolong survival and ameliorate motor deficit through trophic support in Huntington’s disease mouse models. PLoS ONE 6(8), e22924 (2011).

      •Further evidence of mesenchymal stem cells’ ability to release neurotrophic factors and reduce motor deficits and increase the lifespan following transplantation into transgenic mouse models of HD.

    1. Sadan O, Shemesh N, Barzilay R et al. Mesenchymal stem cells induced to secrete neurotrophic factors attenuate quinolinic acid toxicity: a potential therapy for Huntington’s disease. Exp. Neurol 234(2), 417–427 (2012).
    1. Snyder BR, Chiu AM, Prockop DJ, Chan AWS. Human multipotent stromal cells (MSCs) increase neurogenesis and decrease atrophy of the striatum in a transgenic mouse model for Huntington’s disease. PLoS ONE 5(2), e9347 (2010).
    1. Edalatmanesh M-A, Matin MM, Neshati Z, Bahrami A-R, Kheirabadi M. Systemic transplantation of mesenchymal stem cells can reduce cognitive and motor deficits in rats with unilateral lesions of the neostriatum. Neurol. Res 32(2), 166–172 (2010).
    1. Bae KS, Park JB, Kim HS, Kim DS, Park DJ, Kang SJ. Neuron-like differentiation of bone marrow-derived mesenchymal stem cells. Yonsei Med. J 52(3), 401–412 (2011).
    1. Black IB, Woodbury D. Adult rat and human bone marrow stromal stem cells differentiate into neurons. Blood Cells. Mol. Dis 27(3), 632–636 (2001).
    1. Sanchez-Ramos J, Song S, Cardozo-Pelaez F et al. Adult bone marrow stromal cells differentiate into neural cells in vitro. Exp. Neurol 164(2), 247–256 (2000).
    1. Woodbury D, Schwarz EJ, Prockop DJ, Black IB. Adult rat and human bone marrow stromal cells differentiate into neurons. J. Neurosci. Res 61(4), 364–370 (2000).
    1. Brazelton TR, Rossi FM, Keshet GI, Blau HM. From marrow to brain: expression of neuronal phenotypes in adult mice. Science 290(5497), 1775–1779 (2000).
    1. Hung S-C, Cheng H, Pan C-Y, Tsai MJ, Kao L-S, Ma H-L. In vitro differentiation of size-sieved stem cells into electrically active neural cells. Stem Cells Dayt. Ohio 20(6), 522–529 (2002).
    1. Jiang Y, Jahagirdar BN, Reinhardt RL et al. Pluripotency of mesenchymal stem cells derived from adult marrow. Nature 418(6893), 41–49 (2002).
    1. Kopen GC, Prockop DJ, Phinney DG. Marrow stromal cells migrate throughout forebrain and cerebellum, and they differentiate into astrocytes after injection into neonatal mouse brains. Proc. Natl Acad. Sci. USA 96(19), 10711–10716 (1999).
    1. Mezey E, Chandross KJ, Harta G, Maki RA, McKercher SR. Turning blood into brain: cells bearing neuronal antigens generated in vivo from bone marrow. Science 290(5497), 1779–1782 (2000).
    1. Muñoz-Elias G, Marcus AJ, Coyne TM, Woodbury D, Black IB. Adult bone marrow stromal cells in the embryonic brain: engraftment, migration, differentiation, and long-term survival. J. Neurosci 24(19), 4585–4595 (2004).
    1. Hardy SA, Maltman DJ, Przyborski SA. Mesenchymal stem cells as mediators of neural differentiation. Curr. Stem Cell Res. Ther 3(1), 43–52 (2008).
    1. Huang W et al. Transplantation of differentiated bone marrow stromal cells promotes motor functional recovery in rats with stroke. Neurol. Res 35, 320–328 (2013).
    1. Lin Q-M. Mesenchymal stem cells transplantation suppresses inflammatory responses in global cerebral ischemia: contribution of TNF-αa-induced protein 6. Acta Pharmacol. Sindoi:10.1038/aps.2012.199 (2013).
    1. Han EY, Chun MH, Kim ST, Lin D. Injection time-dependent effect of adult human bone marrow stromal cell transplantation in a rat model of severe traumatic brain injury. Curr. Stem CellRes. Ther 8, 172–181 (2013).
    1. Uccelli A, Benvenuto F, Laroni A, Giunti D et al. Neuroprotective features of mesenchymal stem cells. Best Pract. Res. Clin. Haematol 24, 59–64 (2011).
    1. Zuccato C, Ciammola A, Rigamonti D et al. Loss of huntingtin-mediated BDNF gene transcription in Huntington’s disease. Science 293(5529), 493–498 (2001).

    1. Zuccato C, Marullo M, Vitali B et al. Brain-derived neurotrophic factor in patients with Huntington’s disease. PLoS ONE 6(8), e22966 (2011).

      ••An all-encompassing manuscript over the role of brain-derived neurotrophic factor’s role in HD. This study provides evidence that BDNF is decreased in Huntington’s patients and that BDNF is highly correlative with disease progression and decreases as the severity increases.

    1. Almeida S, Laço M, Cunha-Oliveira T, Oliveira CR, Rego AC. BDNF regulates BIM expression levels in 3-nitropropionic acid-treated cortical neurons. Neurohiol. Dis 35(3), 448–456 (2009).
    1. Arregui L, Benítez JA, Razgado LF, Vergara P, Segovia J. Adenoviral astrocyte-specific expression of BDNF in the striata of mice transgenic for Huntington’s disease delays the onset of the motor phenotype. Cell. Mol. Neurobiol 31(8), 1229–1243 (2011).
    1. Bemelmans AP, Horellou P, Pradier L, Brunet I, Colin P, Mallet J. Brain-derived neurotrophic factor-mediated protection of striatal neurons in an excitotoxic rat model of Huntington’s disease, as demonstrated by adenoviral gene transfer. Hum. Gene Ther 10(18), 2987–2997 (1999).
    1. Benraiss A, Bruel-Jungerman E, Lu G, Economides AN, Davidson B, Goldman SA. Sustained induction of neuronal addition to the adult rat neostriatum by AAV4-delivered noggin and BDNF. Gene Ther. 19(5), 483–493 (2012).

    1. Benraiss A, Toner MJ, Xu Q et al. Sustained mobilization of endogenous neural progenitors delays disease progression in a transgenic model of Huntington’s disease. Cell Stem Cell 12(6), 787–799 (2013).

      •It further strengthens the hypothesis that if BDNF can be increased in the brain of transgenic HD mice, behavioral deficits and neuropathology will be decreased. The manuscript also presents a mechanism by which BDNF increases endogenous neurogenesis.

    1. Canals JM, Pineda JR, Torres-Peraza JF et al. Brain-derived neurotrophic factor regulates the onset and severity of motor dysfunction associated with enkephalinergic neuronal degeneration in Huntington’s disease. J. Neurosci 24(35), 7727–7739 (2004).
    1. Cepeda C, Starling AJ, Wu N et al. Increased GABAergic function in mouse models of Huntington’s disease: reversal by BDNF. J. Neurosci. Res 78(6), 855–867 (2004).
    1. Gharami K, Xie Y, An JJ, Tonegawa S, Xu B. Brain-derived neurotrophic factor over-expression in the forebrain ameliorates Huntington’s disease phenotypes in mice. J. Neurochem 105(2), 369–379 (2008).
    1. Giampà C, Montagna E, Dato C, Melone MAB, Bernardi G, Fusco FR. Systemic delivery of recombinant brain derived neurotrophic factor (BDNF) in the R6/2 mouse model of Huntington’s disease. PLoS ONE 8(5) e64037 (2013).
    1. Giralt A, Friedman HC, Caneda-Ferrón B et al. BDNF regulation under GFAP promoter provides engineered astrocytes as a new approach for long-term protection in Huntington’s disease. Gene Ther. 17(10), 1294–1308 (2010).
    1. Giralt A, Carretón O, Lao-Peregrin C, Martín ED, Alberch J. Conditional BDNF release under pathological conditions improves Huntington’s disease pathology by delaying neuronal dysfunction. Mol. Neurodegener 6(1), 71 (2011).
    1. Jiang M, Peng Q, Liu X et al. Small-molecule TrkB receptor agonists improve motor function and extend survival in a mouse model of Huntington’s disease. Hum. Mol. Genet 22(12), 2462–2470 (2013).
    1. Kells AP, Fong DM, Dragunow M, During MJ, Young D, Connor B. AAV-mediated gene delivery of BDNF or GDNF is neuroprotective in a model of Huntington disease. Mol. Ther. J. Am. Soc. Gene Ther 9(5), 682–688 (2004).
    1. Kells AP, Henry RA, Connor B. AAV–BDNF mediated attenuation of quinolinic acid-induced neuropathology and motor function impairment. Gene Ther. 15(13), 966–977 (2008).
    1. Lynch G, Kramar EA, Rex CS et al. Brain-derived neurotrophic factor restores synaptic plasticity in a knock-in mouse model of Huntington’s disease. J. Neurosci 27(16), 4424–4434 (2007).
    1. Martire A, Pepponi R, Domenici MR, Ferrante A, Chiodi V, Popoli P. BDNF prevents NMDA-induced toxicity in models of Huntington’s disease: the effects are genotype specific and adenosine A(2A) receptor is involved. J. Neurochem doi: 10.1111/jnc.12177 (2013) (Epub ahead of print).
    1. Pérez-Navarro E, Alberch J, Neveu I, Arenas E. Brain-derived neurotrophic factor, neurotrophin-3 and neurotrophin-4/5 differentially regulate the phenotype and prevent degenerative changes in striatal projection neurons after excitotoxicity in vivo. Neuroscience 91(4), 1257–1264 (1999).
    1. Pérez-Navarro E, Canudas AM, Akerund P, Alberch J, Arenas E. Brain-derived neurotrophic factor, neurotrophin-3, and neurotrophin-4/5 prevent the death of striatal projection neurons in a rodent model of Huntington’s disease. J. Neurochem 75(5), 2190–2199 (2000).
    1. Petersén AA, Larsen KE, Behr GG et al. Brain-derived neurotrophic factor inhibits apoptosis and dopamine-induced free radical production in striatal neurons but does not prevent cell death. Brain Res. Bull 56(3–4), 331–335 (2001).
    1. Reiner A, Wang HB, Del Mar N, Sakata K, Yoo W, Deng YP. BDNF may play a differential role in the protective effect of the mGluR2/3 agonist LY379268 on striatal projection neurons in R6/2 Huntington’s disease mice. Brain Res 1473, 161–172 (2012).
    1. Saylor AJ, McGinty JF. An intrastriatal brain-derived neurotrophic factor infusion restores striatal gene expression in Bdnf heterozygous mice. Brain Struct. Funct 215(2), 97–104 (2010).
    1. Simmons DA, Rex CS, Palmer L et al. Up-regulating BDNF with an ampakine rescues synaptic plasticity and memory in Huntington’s disease knockin mice. Proc. Natl Acad. Sci. USA 106(12), 4906–4911 (2009).
    1. Simmons DA, Belichenko NP, Yang T et al. A small molecule TrkB ligand reduces motor impairment and neuropathology in R6/2 and BACHD mouse models of Huntington’s disease. J. Neurosci 33(48), 18712–18727 (2013).
    1. Todd D, Gowers I, Dowler SJ et al. A monoclonal antibody TrkB receptor agonist as a potential therapeutic for Huntington’s disease. PLoS ONE 9(2), e87923 (2014).
    1. Volpe BT, Wildmann J, Altar CA. Brain-derived neurotrophic factor prevents the loss of nigral neurons induced by excitotoxic striatal-pallidal lesions. Neuroscience 83(3), 741–748 (1998).
    1. Wu C-L, Hwang C-S, Yang D-I. Protective effects of brain-derived neurotrophic factor against neurotoxicity of 3-nitropropionic acid in rat cortical neurons. Neurotoxicology 30(4), 718–726 (2009).
    1. Xie Y, Hayden MR, Xu B. BDNF overexpression in the forebrain rescues Huntington’s disease phenotypes in YAC128 mice. J. Neurosci 30(44), 14708–14718 (2010).
    1. Zuccato C, Liber D, Ramos C et al. Progressive loss of BDNF in a mouse model of Huntington’s disease and rescue by BDNF delivery. Pharmacol. Res 52(2), 133–139 (2005).
    1. Barzilay R, Ben-Zur T, Bulvik S, Melamed E, Offen D. Lentiviral delivery of LMX1a enhances dopaminergic phenotype in differentiated human bone marrow mesenchymal stem cells. Stem Cells Dev. 18(4), 591–601 (2009).
    1. Bauer G, Dao MA, Case SS et al. In vivo biosafety model to assess the risk of adverse events from retroviral and lentiviral vectors. Mol. Ther. J. Am. Soc. Gene Ther 16(7), 1308–1315 (2008).
    1. Joyce N, Annett G, Wirthlin L, Olson S, Bauer G, Nolta JA. Mesenchymal stem cells for the treatment of neurodegenerative disease. Regen. Med 5(6), 933–946 (2010).
    1. Meyerrose T, Olson S, Pontow S et al. Mesenchymal stem cells for the sustained in vivo delivery of bioactive factors. Adv. Drug Deliv. Rev 62(12), 1167–1174 (2010).
    1. Pollock K, Stewart H, Cary W et al. Mesenchymal stem cells engineered to produce BDNF for the treatment of Huntington’s disease. Cell Transplant. 23(6), 780 (2014).
    1. Bachoud-Lévi A-C. Neural grafts in Huntington’s disease: viability after 10 years. Lancet Neurol. 8(11), 979–981 (2009).
    1. Cicchetti F, Lacroix S, Cisbani G et al. Mutant huntingtin is present in neuronal grafts in Huntington disease patients. Ann. Neurol 76(1), 31–42 (2014).
    1. Reuter I, Tai YF, Pavese N et al. Long-term clinical and positron emission tomography outcome of fetal striatal transplantation in Huntington’s disease. J. Neurol. Neurosurg. Psychiatry 79(8), 948–951 (2008).
    1. Pecho-Vrieseling E, Rieker C, Fuchs S et al. Transneuronal propagation of mutant huntingtin contributes to non-cell autonomous pathology in neurons. Nat. Neurosci. 17(8), 1064–1072 (2014).
    1. Kordower JH, Dodiya HB, Kordower AM et al. Transfer of host-derived α synuclein to grafted dopaminergic neurons in rat. Neurohiol. Dis 43(3), 552–557 (2011).
    1. Gallina P, Paganini M, Lombardini L et al. Human striatal neuroblasts develop and build a striatal-like structure into the brain of Huntington’s disease patients after transplantation. Exp. Neurol 222(1), 30–41 (2010).
    1. Brundin P, Barker RA, Parmar M. Neural grafting in Parkinson’s disease problems and possibilities. Prog. Brain Res 184, 265–294 (2010).
    1. Mathews DJH, Sugarman J, Bok H et al. Cell-based interventions for neurologic conditions: ethical challenges for early human trials. Neurology 71(4), 288–293 (2008).
    1. Pullicino PM, Burke WJ. Cell-based interventions for neurologic conditions: ethical challenges for early human trials. Neurology 72(19), 1709 (2009).
    1. Bachoud-Lévi AC, Rémy P, Nguyen JP et al. Motor and cognitive improvements in patients with Huntington’s disease after neural transplantation. Lancet 356(9246), 1975–1979 (2000).
    1. Capetian P, Knoth R, Maciaczyk J et al. Histological findings on fetal striatal grafts in a Huntington’s disease patient early after transplantation. Neuroscience 160(3), 661–675 (2009).
    1. Freeman TB, Cicchetti F, Hauser RA et al. Transplanted fetal striatum in Huntington’s disease: phenotypic development and lack of pathology. Proc. Natl Acad. Sci. USA 97(25), 13877–13882 (2000).
    1. Furtado S, Sossi V, Hauser RA et al. Positron emission tomography after fetal transplantation in Huntington’s disease. Ann. Neurol 58(2), 331–337 (2005).
    1. Hauser RA, Furtado S, Cimino CR et al. Bilateral human fetal striatal transplantation in Huntington’s disease. Neurology 58(5), 687–695 (2002).
    1. Keene CD, Sonnen JA, Swanson PD et al. Neural transplantation in Huntington disease: long-term grafts in two patients. Neurology 68(24), 2093–2098 (2007).
    1. Kopyov OV, Jacques S, Lieberman A, Duma CM, Eagle KS. Safety of intrastriatal neurotransplantation for Huntington’s disease patients. Exp. Neurol 149(1), 97–108 (1998).
    1. Krystkowiak P, Gaura V, Labalette M et al. Alloimmunisation to donor antigens and immune rejection following foetal neural grafts to the brain in patients with Huntington’s disease. PLoS ONE 2(1), e166 (2007).
    1. Rosser AE, Barker RA, Harrower T et al. Unilateral transplantation of human primary fetal tissue in four patients with Huntington’s disease: NEST-UK safety report ISRCTN no 36485475. J. Neurol. Neurosurg. Psychiatry 73(6), 678–685 (2002).
    1. Philpott LM, Kopyov OV, Lee AJ et al. Neuropsychological functioning following fetal striatal transplantation in Huntington’s chorea: three case presentations. Cell Transplant 6(3), 203–212 (1997).
    1. Madrazo I, Franco-Bourland RE, Castrejon H, Cuevas C, Ostrosky-Solis F. Fetal striatal homotransplantation for Huntington’s disease: first two case reports. Neurol. Res 17(4), 312–315 (1995).
    1. Dunnett SB, Carter RJ, Watts C et al. Striatal transplantation in a transgenic mouse model of Huntington’s disease. Exp. Neurol 154(1), 31–40 (1998).
    1. Ryu JK, Kim J, Cho SJ et al. Proactive transplantation of human neural stem cells prevents degeneration of striatal neurons in a rat model of Huntington disease. Neurobiol. Dis 16(1), 68–77 (2004).
    1. Bernreuther C, Dihné M, Johann V et al. Neural cell adhesion molecule L1-transfected embryonic stem cells promote functional recovery after excitotoxic lesion of the mouse striatum. J. Neurosci 26(45), 11532–11539 (2006).
    1. Aubry L, Bugi A, Lefort N, Rousseau F, Peschanski M, Perrier AL. Striatal progenitors derived from human ES cells mature into DARPP32 neurons in vitro and in quinolinic acid-lesioned rats. Proc. Natl Acad. Sci. USA 105(43), 16707–16712 (2008).
    1. Fink KD, Crane AT, Lévêque X et al. Intrastriatal transplantation of adenovirus-generated induced pluripotent stem cells for treating neuropathological and functional deficits in a rodent model of Huntington’s disease. Stem Cells Transl. Med 3(5), 620–631 (2014).
    1. Jeon I, Choi C, Lee N et al. In vivo roles of a patient-derived induced pluripotent stem cell line (HD72-iPSC) in the YAC128 model of Huntington’s disease. Int. J. Stem Cells 7(1), 43–47 (2014).
    1. Lee S-T, Chu K, Park J-E et al. Intravenous administration of human neural stem cells induces functional recovery in Huntington’s disease rat model. Neurosci. Res 52(3), 243–249 (2005).
    1. Yang C-R, Yu RK. Intracerebral transplantation of neural stem cells combined with trehalose ingestion alleviates pathology in a mouse model of Huntington’s disease. J. Neurosci. Res 87(1), 26–33 (2009).
    1. Vazey EM, Chen K, Hughes SM, Connor B. Transplanted adult neural progenitor cells survive, differentiate and reduce motor function impairment in a rodent model of Huntington’s disease. Exp. Neurol 199(2), 384–396 (2006).
    1. Bosch M, Pineda JR, Suñol C et al. Induction of GABAergic phenotype in a neural stem cell line for transplantation in an excitotoxic model of Huntington’s disease. Exp. Neurol 190(1), 42–58 (2004).
    1. Pineda JR, Rubio N, Akerud P et al. Neuroprotection by GDNF-secreting stem cells in a Huntington’s disease model: optical neuroimage tracking of brain-grafted cells. Gene Ther. 14(2), 118–128 (2007).
    1. Song J, Lee S-T, Kang W et al. Human embryonic stem cell-derived neural precursor transplants attenuate apomorphine-induced rotational behavior in rats with unilateral quinolinic acid lesions. Neurosci. Lett 423(1), 58–61 (2007).
    1. Johann V, Schiefer J, Sass C et al. Time of transplantation and cell preparation determine neural stem cell survival in a mouse model of Huntington’s disease. Exp. Brain Res 177(4), 458–470 (2007).
    1. Kawakami M, Yoshimoto T, Nakagata N, Yamamura K-I, Siesjo BK. Effects of cyclosporin A administration on gene expression in rat brain. Brain Inj. 25(6), 614–623 (2011).
    1. Shin E, Palmer MJ, Li M, Fricker RA. GABAergic neurons from mouse embryonic stem cells possess functional properties of striatal neurons in vitro, and develop into striatal neurons in vivo in a mouse model of Huntington’s disease. Stem Cell Rev. 8(2), 513–531 (2012).
    1. Kordower JH, Chen EY, Winkler C et al. Grafts of EGF-responsive neural stem cells derived from GFAP-hNGF transgenic mice: trophic and tropic effects in a rodent model of Huntington’s disease. J. Comp. Neurol 387(1), 96–113 (1997).
    1. Hurlbert MS, Gianani RI, Hutt C, Freed CR, Kaddis FG. Neural transplantation of hNT neurons for Huntington’s disease. Cell Transplant. 8(1), 143–151 (1999).
    1. Armstrong RJ, Watts C, Svendsen CN, Dunnett SB, Rosser AE. Survival, neuronal differentiation, and fiber outgrowth of propagated human neural precursor grafts in an animal model of Huntington’s disease. Cell Transplant. 9(1), 55–64 (2000).
    1. Visnyei K, Tatsukawa KJ, Erickson RI et al. Neural progenitor implantation restores metabolic deficits in the brain following striatal quinolinic acid lesion. Exp. Neurol 197(2), 465–474 (2006).
    1. Leveque X, Fink KD, Rossignol J, Dunbar GL, Lescaudron L. The use of xenotransplantation in neurodegenerative diseases: a way to go? Xenotransplantation 7, 93–107 (2012).
    1. Lévêque X, Mathieux E, Nerrière-Daguin V et al. Local control of the host immune response performed with mesenchymal stem cells: perspectives for functional intracerebral xenotransplantation. J. Cell. Mol. Med 19(1), 124–134 (2014).
    1. Chamberlain G, Wright K, Rot A, Ashton B, Middleton J. Murine mesenchymal stem cells exhibit a restricted repertoire of functional chemokine receptors: comparison with human. PLoS ONE 3(8), e2934 (2008).
    1. Leten C, Roobrouck VD, Struys T et al. Controlling and monitoring stem cell safety in vivo in an experimental rodent model. Stem Cells Dayt. Ohio 32(11), 2833–2844 (2014).
    1. Liu AM, Qu WW, Liu X, Qu C-K. Chromosomal instability in in vitro cultured mouse hematopoietic cells associated with oxidative stress. Am. J. Blood Res 2(1), 71–76 (2012).
    1. Zhou YF, Bosch-Marce M, Okuyama H et al. Spontaneous transformation of cultured mouse bone marrow-derived stromal cells. Cancer Res. 66(22), 10849–10854 (2006).
    1. Murphy KP, Carter RJ, Lione LA et al. Abnormal synaptic plasticity and impaired spatial cognition in mice transgenic for exon 1 of the human Huntington’s disease mutation. J. Neurosci 20(13), 5115–5123 (2000).
    1. Franich NR, Fitzsimons HL, Fong DM, Klugmann M, During MJ, Young D. AAV vector-mediated RNAi of mutant huntingtin expression is neuroprotective in a novel genetic rat model of Huntington’s disease. Mol. Ther 16(5), 947–956 (2008).
    1. Paulsen JS, Langbehn DR, Stout JC et al. Detection of Huntington’s disease decades before diagnosis: the predict-HD study. J. Neurol. Neurosurg. Psychiatry 79(8), 874–880 (2008).
    1. Aylward EH. Change in MRI striatal volumes as a biomarker in preclinical Huntington’s disease. Brain Res. Bull 72(2–3), 152–158 (2007).
    1. Túnez I, Tasset I, Pérez-De La Cruz V, Santamaría A. 3-nitropropionic acid as a tool to study the mechanisms involved in Huntington’s disease: past, present and future. Mol. Basel Switz 15(2), 878–916 (2010).
    1. Shear DA, Haik KL, Dunbar GL. Creatine reduces 3-nitropropionic-acid-induced cognitive and motor abnormalities in rats. Neuroreport 11(9), 1833–1837 (2000).
    1. Ayalon L, Doron R, Weiner I, Joel D. Amelioration of behavioral deficits in a rat model of Huntington’s disease by an excitotoxic lesion to the globus pallidus. Exp. Neurol 186(1), 46–58 (2004).
    1. Kalonia H, Kumar P, Nehru B, Kumar A. Neuroprotective effect of MK-801 against intra-striatal quinolinic acid induced behavioral, oxidative stress and cellular alterations in rats. Indian J. Exp. Biol 47(11), 880–892 (2009).
    1. Velloso NA, Dalmolin GD, Gomes GM et al. Spermine improves recognition memory deficit in a rodent model of Huntington’s disease. Neurobiol. Learn. Mem 92(4), 574–580 (2009).
    1. Fink KD, Rossignol J, Crane AT et al. Early cognitive dysfunction in the HD 51 CAG transgenic rat model of Huntington’s disease. Behav. Neurosci 126(3), 479–487 (2012).
    1. Jansson EKH, Clemens LE, Riess O, Nguyen HP. Reduced motivation in the BACHD rat model of Huntington disease is dependent on the choice of food deprivation strategy. PLoS ONE 9(8), e105662 (2014).
    1. Von Hörsten S, Schmitt I, Nguyen HP et al. Transgenic rat model of Huntington’s disease. Hum. Mol. Genet 12(6), 617–624 (2003).
    1. Yu-Taeger L, Petrasch-Parwez E, Osmand AP et al. A novel BACHD transgenic rat exhibits characteristic neuropathological features of Huntington disease. J. Neurosci 32(44), 15426–15438 (2012).
    1. Carter RJ, Lione LA, Humby T et al. Characterization of progressive motor deficits in mice transgenic for the human Huntington’s disease mutation. J. Neurosci 19(8), 3248–3257 (1999).
    1. Schilling G, Becher MW, Sharp AH et al. Intranuclear inclusions and neuritic aggregates in transgenic mice expressing a mutant N-terminal fragment of huntingtin. Hum. Mol. Genet 8(3), 397–407 (1999).
    1. Slow EJ, van Raamsdonk J, Rogers D et al. Selective striatal neuronal loss in a YAC128 mouse model of Huntington disease. Hum. Mol. Genet 12(13), 1555–1567 (2003).
    1. Gray M, Shirasaki DI, Cepeda C et al. Full-length human mutant huntingtin with a stable polyglutamine repeat can elicit progressive and selective neuropathogenesis in BACHD mice. J. Neurosci 28(24), 6182–6195 (2008).
    1. Lin CH, Tallaksen-Greene S, Chien WM et al. Neurological abnormalities in a knock-in mouse model of Huntington’s disease. Hum. Mol. Genet 10(2), 137–144 (2001).
    1. Beal MF, Kowall NW, Ellison DW, Mazurek MF, Swartz KJ, Martin JB. Replication of the neurochemical characteristics of Huntington’s disease by quinolinic acid. Nature 321(6066), 168–171 (1986).
    1. Hamilton BF, Gould DH. Nature and distribution of brain lesions in rats intoxicated with 3-nitropropionic acid: a type of hypoxic (energy deficient) brain damage. Acta Neuropathol. (Berl.). 72(3), 286–297 (1987).
    1. Yang D, Wang C-E, Zhao B et al. Expression of Huntington’s disease protein results in apoptotic neurons in the brains of cloned transgenic pigs. Hum. Mol. Genet 19(20), 3983–3994 (2010).
    1. Jacobsen JC, Bawden CS, Rudiger SR et al. An ovine transgenic Huntington’s disease model. Hum. Mol. Genet 19(10), 1873–1882 (2010).
    1. Yang S-H, Cheng P-H, Banta H et al. Towards a transgenic model of Huntington’s disease in a non-human primate. Nature 453(7197), 921–924 (2008).
    1. Morton AJ, Howland DS. Large genetic animal models of Huntington’s Disease. J. Huntingt. Dis 2(1), 3–19 (2013).
    1. Isakova IA, Baker K, Dufour J, Gaupp D, Phinney DG. Preclinical evaluation of adult stem cell engraftment and toxicity in the CNS of rhesus macaques. Mol. Ther. J. Am. Soc. Gene Ther 13(6), 1173–1184 (2006).
    1. Isakova IA, Dufour J, Lanclos C, Bruhn J, Phinney DG. Cell-dose-dependent increases in circulating levels of immune effector cells in rhesus macaques following intracranial injection of allogeneic MSCs. Exp. Hematol 38(10), 957–967.e1 (2010).
    1. Isakova IA, Lanclos C, Bruhn J et al. Allo-reactivity of mesenchymal stem cells in rhesus macaques is dose and haplotype dependent and limits durable cell engraftment in vivo. PLoS ONE 9(1), e87238 (2014).
    1. Gothelf Y, Abramov N, Harel A, Offen D. Safety of repeated transplantations of neurotrophic factors-secreting human mesenchymal stromal stem cells. Clin. Transl. Med 3, 3 (2014).
    1. Hess DC, Sila CA, Furlan AJ, Wechsler LR, Switzer JA, Mays RW. A double-blind placebo-controlled clinical evaluation of MultiStem for the treatment of ischemic stroke. Int. J. Stroke 9(3), 381–386 (2014).
    1. Alper J Geron gets green light for human trial of ES cell-derived product. Nat. Biotechnol 27(3), 213–214 (2009).

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