Open access peer-reviewed chapter

Cell Therapy in Huntington’s Disease

Written By

Hyun Sook Kim and Jihwan Song

Submitted: October 24th, 2014 Reviewed: April 13th, 2015 Published: December 2nd, 2015

DOI: 10.5772/60618

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Huntington’s disease (HD) is a rare neurodegenerative disease inherited in an autosomal dominant pattern. Expanded cytosine-adenine-guanine (CAG) repeats (polyQ) in the huntingtin gene cause the aggregates of abnormally expanded polyQ-containing huntingtin protein, and striatal medium spiny neurons are shown to be the most vulnerable. Affected patients develop cognitive, motor, and psychiatric symptoms typically in middle age, and several pharmacological drugs are currently used for symptomatic relief. Since the effect of current therapies is very limited and there is no way to modify disease progression, there is an unmet need for developing new therapies for HD. Toxin or genetic rodent models are widely used for drug development, and large animal models are also available. Previous studies transplanting cells originating from embryonic or fetal striatal tissues, neural stem cells, mesenchymal stem cells, and induced pluripotent stem cells (iPSCs) in HD animal models have shown the possibilities of clinical trials. Because clinical trials performed using human fetal striatal cells have shown variable outcomes, future directions of cell therapy in HD should consider the reconstitution of a functional dynamic information-processing circuit without ectopic connections. Another major challenge is to achieve controlled differentiation of embryonic stem cells or iPSCs into specific neuronal phenotypes.


  • Huntington’s disease
  • Animal models
  • Stem cells
  • Cell therapy
  • Transplantation

1. Introduction

Huntington’s disease (HD) is an inherited neurodegenerative disease caused by expanded CAG repeats in the huntingtin gene (Htt) on chromosome 4, which give rise to the formation of aggregates of mutant huntingtin proteins. Affected patients gradually develop cognitive decline, motor dysfunction (i.e., chorea or bradykinesia), and psychiatric disturbance that lead to progressive disability and death within approximately 15–20 years of disease onset. Since Huntington’s disease is inherited in an autosomal dominant manner (i.e., 50 % of children are at risk) and the symptom onset occurs typically in middle age (median age, 35–40 years), affected patients and their family members suffer from significant economical and psychological burdens. Unfortunately, current therapies only target symptomatic reliefs and their effects are very limited, so the need for developing new therapies for HD is in high demand.

It is important to rescue these vulnerable medium spiny neurons (MSNs) by slowing the inexorable loss of striatal neurons and to delay the loss of striatal volume in affected patients, in view of HD pathology where striatal MSNs are shown to be most affected. More recently, stem cell strategy has been proposed to restore GABAergic striatal projection neurons into the putamen and the caudate, thereby reestablishing the degenerating striatopallidal circuit. According to previous research, transplanted cells originating from embryonic or fetal striatal tissues in HD animal models are connected with appropriate targets in the host brain and function both electrophysiologically and neurochemically to certain extents. Although clinical trials based on these preclinical studies have been performed using human fetal striatal cells, they have shown variable outcomes: some describe no benefit while others have indicated some clinical improvements with reduced motor dysfunction or slowed disease progression. However, because the use of human fetal tissues raise ethical issues and their genetic dissimilarity to the recipient is associated with the risk of immune rejection, other suitable non-fetal cell sources of syngeneic donor tissue would be advantageous. Recently, although induced pluripotent stem cells (iPSCs) generated from skin fibroblasts of HD patients have been demonstrated as an alternative autologous cell source, these HD patient-derived iPSCs carry genetic mutations, meaning that they have to be corrected to normal genes in order to be used for cell therapy. For clinical applications, it will be essential to use transgene-free reprogrammed iPSCs that are derived from patients under good manufacturing protocol (GMP) conditions. In addition to this iPSC approach, it may be worthwhile to consider using mesenchymal stem cells (MSCs), which are widely used in clinical trials, for the treatment of HD.

In this review, we describe the characteristics and limitations of current therapeutics and the need for developing novel ones. Then, animal models commonly used in HD research, various cell sources for transplantation, and the results and problems of preclinical and clinical studies so far are also discussed. Finally, we discuss the future directions of HD research and the clinical applications of stem cells. By doing so, we aim that the readers can acquire a thorough knowledge of HD and an understanding of the need for and the current view of cell therapy in HD.


2. Characteristics of Huntington’s Disease

Huntington’s disease (HD) is a progressively deteriorating neurodegenerative disorder caused by expanded polyglutamines (polyQs) with more than 35 CAG repeats in the huntingtin gene (Htt) on chromosome 4. Htt protein is approximately 350 kDa and is composed of ten HEAT (huntingtin, elongation factor 3, protein phosphatase 2A, and the yeast P13-kinase TOR1) repeats, which form α-helical structures participating in intracellular transport [1]. Htt protein is a ubiquitously expressed soluble protein [2]. Cytosolic Htt has been shown to bind microtubules and vesicles [3], whereas up to 5 % of Htt protein has been shown to locate within the nucleus [4]. Htt protein is known for its involvement in microtubule-mediated vesicle transport, endocytosis, secretory process, and regulation of gene transcription/RNA trafficking, in line with its location within the cell [5].

Interference with transcriptional regulation (e.g. CREB)
Decline of neurotransmitter receptors and brain-derived neurotrophic factor (BDNF) level
Interference with chaperone, proteasome (UPS), and autophagy activities
Disrupted axonal transport and synaptic transmission; cytoplasmic sequestration of transcription factors
Mitochondrial (complex I/II) dysfunction: calcium dysregulation/defective energy metabolism
Excitotoxicity via NMDA glutamate receptors
Activation of microglia and macrophages
Increased Kynurenine 3-monooxygenase (KMO) and 3-hydroxykynureine production: oxidative stress

Table 1.

Pathologic mechanisms of Huntington’s disease

It is still under debate whether the effect of mutant Htt protein is through a “gain-of-toxic function” or a “loss of function,” and various mechanisms have been suggested to elucidate the pathologic mechanisms of HD (Table 1). For example, mutant Htt that is translocated into the nucleus can interfere with gene transcription via either direct binding to DNA or interacting with several mediators including CBP (cAMP response element binding protein), NCoR (nuclear receptor corepressor), SP1 transcription factor, basal transcription factors, and REST (repressor element 1 silencing transcription factor) element [6, 7]. This reduced transcription can decrease the level of brain-derived neurotrophic factor (BDNF) in the brain of HD patients. Other loss-of-function mechanisms of Htt for disease pathogenesis have also been proposed [8, 9]. It is worth noting that Htt is necessary for early embryonic development and Htt-null mice demonstrate increased apoptosis [10]. A “gain-of-toxic-function” is another important mechanism of toxicity of mutant Htt. For instance, because a highly expanded Htt gene in HD leads to an Htt protein containing an abnormally expanded polyQ segment, toxic N-terminal fragments of abnormal ß-sheets are formed [11]. Other posttranslational factors also promote toxicity of mutant Htt, such as conformational change, aggregation propensity, cellular localization, and clearance rate. Mutant Htt binds to mitochondria and alters mitochondrial metabolism, which may result in energy defects, oxidative stress, and disturbed calcium homeostasis [12]. Moreover, protein clearance systems are shown to be impaired in HD patients and in models [13]. Irrespective of the mode of patho-mechanism, Htt aggregates within the cytoplasm and the nucleus, and selective neuronal cell loss and atrophy occur predominantly in the striatum and the neocortex [14]. Altogether, HD develops mainly through a “gain-of-toxic-function” mechanism from an abnormal conformation of mutant Htt [15, 16].

HD is an inheritable disease passed down in an autosomal dominant manner. The prevalence of HD is 4–10 per 100,000 in Western countries and approximately 0.4 per 100,000 in Asian countries [17]. Disease onset is typically in middle age (median age, 35–40 years), but it can also occur less commonly in juveniles and in old age depending on the CAG repeat number and/or modifying genes and environmental factors [18]. The studies on the relationship between CAG repeat number and disease manifestation demonstrated that there is an inverse correlation between age at initial symptom onset and the length of the expanded CAG repeat [19], and the correlation determines the age of onset with approximately 50–60 % variation [20, 21]. During HD, the disruption of the corticostriatal pathway, the main pathway affected, causes progressive cognitive decline, motor dysfunction, psychiatric disturbance, and ultimately death within approximately 15–20 years [22]. Although CNS degeneration attributes to these core symptoms, widespread pathology throughout the body may also contribute to other general symptoms such as weight loss, skeletal muscle wasting, metabolic and endocrine dysfunction, and dysfunction of cells of the hematopoietic lineage [13, 23].

Large aggregates of abnormally expanded polyQ-containing Htt protein, which form intranuclear inclusion bodies, are the pathological signatures of HD. Although the aggregates of mutant Htt are widespread throughout the brain and body, the striatum-selective damage encompassing the loss of striatal volume and up to 95 % loss of GABAergic medium spiny neurons (MSNs) is seen in the corticostriatal pathway [24]. This striatal selectivity might be explained by a possible involvement of a Ras homolog enriched in striatum (Rhes), a striatal-specific protein that binds to mutant Htt and increases the cytotoxicity of Htt through SUMOylation in HD pathogenesis [25]. Other than SUMOylation by Rhes, posttranslational modifications generally on the N-terminal 17 amino acids of Htt, including phosphorylation, ubiquitination, palmitoylation, and SUMOylation of huntingtin-associated (interacting) proteins, have important roles in modulating the toxicity of Htt as well as the selective neuronal loss [26]. Among the posttranslational modifications, phosphorylation has been shown as the major process for modulating Htt. Phosphorylation at serines 13 and 16 of Htt has been demonstrated to be protective against motor and psychiatric dysfunction and neuropathology [27]. Palmitoylation of Htt at cystein 214 has been shown to enhance its membrane association, whereas an expanded Htt shows less palmitoylation and an associated increase in neuronal toxicity [28]. Small ubiquitin-like modifiers (SUMO) are proteins that covalently attach to and detach from the target protein to modify their function, a process described as SUMOylation. Several SUMO proteins are known to interact with Htt-related proteins (huntingtin-associated protein 1 (HAP1) and transcription elongation regulator 1) [13], and SUMOylation of these proteins by SUMO may be related to the pathogenesis of HD. Lastly, a disruption of BDNF support or an increased susceptibility to glutamatergic excitotoxicity of the neuronal circuit between the cerebral cortex and the striatum can lead to HD pathogenesis [29].

In HD pathogenesis, selective striatal neuronal loss comes not only from cell-autonomous toxicity but also cell-cell interactions. Cell-cell interactions occur between both interneuronal connections and between glial cells and neurons. In interneuronal connections, mutant Htt causes increased stimulation of extrasynaptic glutamate receptors and a decreased reuptake of glutamate by glia, leading to enhanced excitotoxicity and metabolic toxicity. Neuron and glia coculture experiments showed that expressing mutant Htt in glia triggered neuronal death only in cells expressing mutant Htt, providing evidence for the role of mutant Htt in neuronal excitotoxicity [30]. Further, HD patient-derived astrocytes alone were shown to replicate HD pathology when Htt with expanded CAG repeats was expressed [31]. Similarly, in astrocytes, transgenic expression of mutant Htt alone led to HD-like symptoms or worsened disease progression when crossed into existing HD models or even into normal mice [32]. In HD patients, microglia are activated in prodromal stages, and then symptoms manifest in HD. The level of microglial activation has been shown to correlate with disease severity and striatal loss in vivo [33, 34].


3. Current therapeutics in clinical practice and its limitation: Need for developing novel therapeutics

Several pharmacological drugs are currently used for symptomatic relief of HD symptoms such as hyperkinetic involuntary movements and mood disorders, and there is no way to modify disease progression. For hyperkinetic involuntary movements including chorea, myoclonus, and dystonia, dopamine-depleting agents (tetrabenazine), antipsychotics (haloperidol, pimozide, clozapine, olanzapine, ziprasidone, aripiprazole, risperidone, and quetiapine), benzodiazepines (clonazepam), anticonvulsants (sodium valproate and levetiracetam), and botulinum toxin can be prescribed. Because tetrabenazine is not only a dopamine-depleting agent but may also decrease brain serotonin and norepinephrine concentrations, it potentially causes or aggravates depression [35]. Various neuroleptics (olanzapine, quetiapine, risperidone, sulpiride, haloperidol, and clozapine) that are also used for psychiatric symptoms should be administered with caution because they may induce tardive dyskinesia and other adverse effects. Clozapine is well known for being costly and inducing irreversible agranulocytosis. For mood disorders, antidepressants (citalopram, fluoxetine, paroxetine, sertraline, mirtazapine, and venlafaxine) and anxiolytics (benzodiazepines, propranolol, and clonidine) are used [13]. A range of psychiatric drugs can alleviate some of the more overt disturbances of mood and hyperactivity in HD; however, these drugs have limited effects and are associated with side effects [36]. There is limited evidence in the literature for the use of acetylcholinesterase inhibitor (rivastigmine and donepezil) for cognitive dysfunction in HD [36, 37].

Behavioral and social interventions are often as effective as drug therapy for behavioral difficulties. For instance, weight loss frequently leads to general weakening [38] and a higher body mass index has been associated with a slower rate of disease progression [39], meaning that adequate nutrition may be another important aspect of therapy. Other than nutrition, environmental enrichment and physical, speech, and occupational therapy are also usually recommended to delay the onset of HD, some of which have been validated in mouse models [40, 41].

HD is one of few neurodegenerative diseases for which the diagnosis can be made long before the onset of clinical symptoms by predictive genetic testing. This offers an opportunity to intervene in the earliest stages of neurodegeneration and thereby slow down or arrest disease progression. Many drugs targeting various mechanisms underlying HD pathogenesis have been tested. However, antiexcitotoxic drugs, such as riluzole (an antiglutamatergic drug) [42], vitamin E [43], idebenone and remacemide (an NMDA ion channel blocker) [44], minocycline (a caspase-3 inhibitor and anti-inflammatory agent) [45], and creatine (energy metabolites, CREST-E trial) [46] have failed in clinical trials so far. More favorable results from animal studies using memantine (an NMDA receptor antagonist), coenzyme Q10 (a mitochondrial cofactor and an antioxidant), and ethyl eicosapentaenoate (an antioxidant) have been highlighted, but none of these compounds was successful. Currently, reducing the expression of mutant Htt protein with RNA interference or antisense oligonucleotides is the most promising candidate and other approaches of various mechanisms are being designed and under investigation [47].


4. Animal models of Huntington’s Disease

4.1. Rodent models in Huntington’s Disease

Rodent models have played an important role in providing experimentally accessible systems to study various clinicopathological findings and pathogenesis of HD and to test potential therapeutics of their efficacy [48]. From the late 1970s, several investigations started to generate animal models of HD. Glutamate-related excitotoxin kainic acid (KA) and quinolinic acid (QA) were used to induce the degeneration of striatal GABAergic projection neurons while preserving striatal afferents, thereby producing a model that resembles the neuropathologic condition in HD [49, 50]. Because of marked epileptogenic side effects in KA model, QA model is favored and currently used. Another toxic model of HD is made by producing defective energy metabolism through toxins such as sodium azide, malonate, and 3-nitropropionic acid (3-NP). For example, 3-NP-induced inhibition of mitochondrial complex II effectively produces striatal lesions that were similar to the cell loss in HD [51, 52]. To mimic the chronic progressive nature of human HD, chronic administration of metabolic toxin has been tried in experimental primates; however, higher inter-animal variability and nonspecific striatal damage in primates (NO replacement; just delete please) limit this approach [53]. Altogether, despite their usefulness as mimics of striatal pathology and behavioral manifestations of HD, toxin models were limited because it was not possible to study disease progression or to replicate the widespread neuropathology observed in the human condition [54].

After the discovery of the HD gene in 1993, genetic models of HD have been generated, and over 20 different rodent models have been generated to date [55]. Genetic models provide accurate and experimentally accessible systems in which to study the molecular pathogenesis. Moreover, they provide an opportunity to test the effect/efficacy of candidate therapeutics and explore their potential for clinical applications. Because the degree of overexpression of mutant Htt protein plays a significant role in the phenotype in mice, genetic mouse lines have been generated with varying degrees of phenotype by incorporating variations of mutant huntingtin gene into the mouse genome. The mouse models fall into three categories (Table 2): (i) mice that express truncated N-terminal fragment (exon-1 or exons 1 and 2) of the human Htt gene containing polyglutamine mutations [56-60]; (ii) mice that express the full-length human HD gene [61-65]; and (iii) mice with pathogenic human CAG repeats inserted into the existing CAG expansion in murine Htt (knock-in models) [66-70]. Although all of these models develop the typical findings of human HD, the degree and the progression to which the behavioral features and pathological findings manifest differ, as well as the developmental speeds. Among them, the R6/2 mice showed the most prominent motor, behavioral, and cognitive phenotypes as well as marked weight loss and death by 13~15 weeks of age. In this strain, various mechanisms of HD pathogenesis are demonstrated, including the intraneuronal nuclear inclusions; impaired mitochondrial function [71]; abnormalities of glutamatergic, dopaminergic, and cholinergic receptors in the striatum [72]; and abnormalities in synaptic plasticity in the hippocampus [73, 74]. The full-length Htt gene (transgene) is incorporated into the mouse genome via bacterial artificial chromosome (BAC) or yeast artificial chromosome (YAC). Meanwhile, the phenotypes in the full-length Htt mutation model develop gradually over several months and may survive as long as the wild-type animal [75]. This model is especially valuable for studies on the proteolytic mechanism of full-length Htt, its clearance, and the evaluation of the presymptomatic stages of HD. Among the full-length HD genetic models, the YAC mouse model with 128 CAG repeats (YAC128) develops motor abnormalities, composing of an initial hyperactivity and followed by difficulty in motor control from six to 12 months and then hypokinesia [76]. Further, other motor dysfunctions, including circling behavior, hind limb clasping, and gait abnormalities, may be seen as early as three months [77]. Although the full-length models are genetically more accurate, the fragment Htt models have been used more frequently for their aggressive phenotype, rapidly progressive disease course, well-defined behavioral and pathological findings, and early death. Moreover, due to the prolonged disease progression in the full-length Htt models, it is hardly possible to use progressive morbidity and survival as endpoints [53].

While toxin models play a role in understanding mechanisms of excitotoxicity and mitochondrial dysfunction in HD, they cannot replicate the progressive neurodegenerative course characterized by the misfolding of the mutant Htt protein in HD. Alternatively, genetic animal models provide a good platform to explore the progressive manifestation of neuropathology and cognitive, behavioral, and motor dysfunction [48]. It also provides the platform to test potential therapeutics for future translational research. However, standardization of sample size, inclusion/exclusion criteria of mice, and the onset and duration of treatment, as well as the outcome measurement of preclinical trials, are critical to compare the effectiveness of candidate therapeutics [78].

Model CAG-N Behavioral changes Neuropathology Survival
Transgenic models: Truncated N-terminal fragment
R6/1, Mouse
[56, 57]
116 Decreased anxiety
Significant weight loss
Abnormal motor performance
Reduced brain volume
Loss of striatal neurons
Htt aggregates
Reduced dopamine levels
12+ months
R6/2, Mouse
144–150 Dystonia with limb clasping
Significant weight loss
Reduced motor performance
Seizures, Diabetes
Gross brain atrophy
Progressive neuronal atrophy with neuronal loss
Htt aggregates
Reduced dopamine levels
12–18 weeks
N171-82Q, Mouse [59] 82 Weight loss
Abnormal motor performance
Limb clasping
Visuospatial memory loss
Gross brain atrophy
Atrophy and loss of striatal neuron
Htt aggregates
130–180 days
HD51, Rat [60] 51 Significant weight loss
Deficient motor performance
Reduced anxiety
Cognitive deficits
Head dyskinesias
Enlarged ventricles
Striatal neuronal loss
Htt inclusion
Transgenic mouse models: Full-length human Htt
YAC 128
[62, 76]
128 Hyperactivity (initial); hypokinesia (later)
Abnormal circling behavior
Hindlimb clasping
Deficient motor performance
Gait abnormalities
Decreased striatal and cortical volume
Reduced striatal neuron area and number
Progressive Htt aggregates
Slightly decreased
[64, 78]
97 (Mixed CAA/CAG repeat) Significant reduction in motor function (2 months)
Behavioral worsening (12 months)
Marked gross brain atrophy and brain weight loss
Significant cortical and striatal volume loss (12 months)
Degenerating neurons in striatum (12 months)
Htt inclusions in entire cortex; a few small inclusions in striatum
Normal lifespan
97 Motor learning deficit (2 months)
Deficits in both spatial learning and object recognition (9 months)
Increased stereotypy or repetitive movement
Anxious and depressive-like behaviors
Forebrain atrophy
Striatal volume loss
Cortical shrinkage and white matter loss (12 months)
Knock-in mouse models: Full-length Htt
[66, 68]
111 Gait impairment (13 months) Diffuse Htt activity (6 weeks) with nuclear inclusions (12 months)
Astrogliosis (24 months)
Normal life span
CAG140 [69] 140 Body weight loss
Hyperactivity (initial); hypoactivity (later)
Gait abnormalities (12 months)
Nuclear and neuropil aggregates (8 months)
Diffuse Htt (2 months)
Neuronal loss
Normal life span
CAG150 [70] 150 Body weight loss (70 weeks)
Motor performance deficits on rotarod, gait, and beam balance (70–100 weeks)
Striatal Htt aggregates (28 weeks)
Nuclear inclusions (37 weeks)
Reactive astrogliosis (56 weeks)
Loss of striatal neuron perikarya and volume (100 weeks in homozygous mice)
Normal life span

Table 2.

Rodent models of Huntington’s disease

Htt=huntingtin protein; NA=not available

4.2. Large animal models in Huntington’s Disease

Nonhuman primates are genetically more similar and have a more similar physiology to humans than rodents, making them invaluable for modeling human disorders and for developing therapeutic strategies. Nevertheless, only a limited number of works has been reported in HD. The use of nonhuman primates is focused on the study of HD-like behavioral manifestations, especially for chorea, and the development of potential therapeutics for HD. In the case of nonhuman primate study, the toxin models using QA or 3-NP were most commonly used [52, 79]. After the development of transgenic nonhuman primate models of HD in 2008, the potentials of using large animals in HD research have been spotlighted. There are three types of large animal models: a rhesus monkey (Macaca mulatta) [80], a miniature pig model [81], and a sheep model (Ovis aries) [82]. The rhesus macaque and pig models were generated using fragments of human mutant Htt and the sheep model using the full-length human coding sequence of Htt. By injecting oocytes with lentiviruses expressing exon1 of Htt carrying 84 CAG repeats, three transgenic monkeys were made, which survived for more than two years and showed clinical features of HD, including dystonia and chorea [80]. Transcriptomic dysregulation was recently reported from peripheral blood samples, which is under further clinical investigations [83]. The transgenic HD sheep model demonstrated a decreased expression of DARPP-32 (dopamine- and cAMP-regulated phosphoprotein of 32 kDa) at seven months of age and a characteristic inclusion pathology in the brain at 18 months [84].On the contrary, there were no aggregates in the brain even up to 16 months of age and no development of motor abnormalities in transgenic minipigs [85]. Because transgenic large animal models have many advantages to understand the biology of HD and the development of potential therapies, practical and ethical issues as well as preclinical works should be also considered.


5. Source of cell therapy for striatal transplantation in HD

A characteristic pathological feature in Huntington’s disease is a selective loss of medium spiny projection neurons (MSN) in the striatum. Thus, cell therapy in HD is aimed at replacing the MSN and making them functionally active by connecting them to the host neuronal network [86]. To accomplish this, transplanted cells should survive, differentiate in vivo into the proper cell type (i.e., MSN), be functionally active, and connect with appropriate target neurons, thereby reestablishing the degenerating striatopallidal circuit [87, 88]. A number of potential stem/progenitor cells have been studied that include embryonic stem cells; multipotent progenitor cells from the embryo or fetus, which are already partially committed to a neural lineage; cells from the umbilical blood; autologous or allogenic adult stem cells from various tissues; and finally induced pluripotent stem cells [53]. The majority of cells used so far are fetal neural stem/progenitor cells, but adult stem cells or iPSCs can be alternative cell sources to fetal or embryo-derived stem cells. Before starting clinical trials, each cell type should be shown to have efficacy and long-term safety in properly designed animal models of HD.

5.1. Fetal neural stem cells and fetal neural progenitor cells

Fetal neural stem cells (NSCs) are isolated from the fetal brain at various gestational periods and from multiple brain regions [89]. After the collection of primitive cells and their short-term expansion in vitro, these cells are transplanted into the lesioned brain of an adult rodent. Majority of previous studies have used fetal neural progenitors (FNPs), which are expanded as neurospheres prior to transplantation (Table 3), and the transplanted FNPs showed evidence of differentiation into striatal-like cells [90]. Such neural differentiation depends on the characteristics of fetal neural stem/progenitor cells to respond to signals in the developing CNS [91]. For example, stem cells derived from the human fetal cortex (12 weeks post-conception) were pretreated in culture media with ciliary neurotrophic factor (CNTF) and were transplanted into QA-lesioned rats. Motor recovery and sustained striatal volume were marked and the transplanted human stem cells differentiated into neurons and astrocytes with substantial connections to endogenous cells [92]. Systemic injection of human NSC also improved neuropathologic and behavioral abnormalities [93]. Because HD showed a selective loss of MSNs in the striatum, induction of a GABAergic phenotype in immortalized striatal NSCs was tried. These GABAergic phenotype-induced cells maintained neurite processes connecting to endogenous neurons [94]. Mouse NSCs modified to secrete human nerve growth factor (NGF) were transplanted into striatal QA-lesioned rats, and it was shown that the size of lesion, the number of surviving striatal neurons, and the length of neurites were significantly improved than sham-operated rats [95]. However, despite these successes based on fetal stem/progenitors, the use of in vitro expanded fetal neural stem cells is limited because they lose the capacity to differentiate into various neural cell types and tend to go into senescence after several passages of culture [96]. Moreover, there is an intrinsic ethical issue associated with the use of aborted fetal tissue. Recently, a cloned human striatal neural stem cell line (STROC05) was transplanted in the R6/2 mouse model of HD, but the mouse model showed a disappointing suboptimal clinicopathological improvement [97] (Table 3).

Animal model Cells Histology Functional outcome Ref
Rat, QA [U] Human stem cell-derived from fetal cortex (pretreated with CNTF) Reduced striatal atrophy
Survive and differentiate into neuron and glia
Connectivity with endogenous neural cells
Improved motor performance (cylinder test) [92]
Rat, QA [U] Human NSC-derived from fetal human brain (systemic injection) Reduced striatal atrophy
NSC migration in and around the damaged striatum
Migrated NSCs differentiated into neurons and glias
Reduced ApoM-induced rotation [93]
Mice, QA [U]
Mouse NSC - neurosphere and dissociated cell suspension Increased survival of graft when transplant at 2 days after lesioning No change on BDNF expression [94]
Rat, QA Noggin-primed human NPC derived from human ESC Extensive migration and large-scale differentiation
Increased the extent of neuronal differentiation
NA [102]
R6/2 undifferentiated or predifferentiated DARPP-32 cells [B] derived from human striatal neural stem cell line (STROC05) Poor survival and neuronal differentiation both in the undifferentiated and differentiated conditions
A few cells expressed the neuronal marker beta-III-tubulin.
NA [97]
Rat, Lesions of the dorsal striatum [U] Homotopic neural transplants
(GE or cortex from E15 rat embryos of same strain)
Patches of positive DARPP-32 and tyrosine hydroxylase
Significantly higher extent of DARPP-32 patches
Alleviated lateralised response deficits
Prevented development of lateral disparity
Restored speed of responding back to pre-lesion levels
Rat, KA Fetal rat striatal primordia Differentiation to spiny neuron Restored synaptic potential [135]
Rat, QA Embryonic striatal grafts (Lateral GE) Reversed lesion-induced increase in the cytochrome oxidase activity of the Gp Reduction of ApoM-induced rotational asymmetry [136]
Rat, Ch Embryonic striatum Innervated by host-derived dopamine axons Restored response of host neurons [137]
Rat, KA Fetal striatal graft NA Restored striatal GABA overflow [138]
Rat, IA [U] Embryonic striatal graft NA Stimulation of GABA release [139]
R6/2 Striatal grafts Survival and differentiation of grafts Improved general locomotor behavior
No significant functional improvement
R6/1 Wild-type donor cortex NA No improvement [133]
Rat, 3-NP Human NSC (transplantation before 3-NP administration) Reduced damage to striatal neurons
Increased BDNF expression
Improved motor performance [140]

Table 3.

Neural stem cell/progenitor cell-based treatment of HD in preclinical rodent models

Apo-M=apomorphin; BDNF=brain-derived neurotrophic factor; BM-MSCs=bone-marrow-derived mesenchymal stem cells; Ch= Cholecystokinin-8-sulphate; CNTF=ciliary neurotrophic factor; DARP-32=dopamine- and cAMP-regulated phosphoprotein of 32 kDa; ESC=embryonic stem cell; GABA=gamma-aminobutyric acid; GE=ganglionic eminence; Gp=globus pallidus; IA=ibotenic acid; KA=kainic acid; 3NP=3-nitropropionic acid; MSN=medium spiny neuron; NA=not available; NPC=neural precursor cell; NSC=neural stem cell; QA=Quinolinic acid; [B]=bilateral; [U]=unilateral

5.2. Embryonic stem cell-derived neural progenitor cells

Embryonic stem cells (ESCs) are isolated and expanded from the inner cell mass of the blastocyst-stage embryo. Because ESCs are very primitive and pluripotent, they can be expanded in vitro indefinitely while retaining relatively stable cell characteristics [98]. Even after expansion, they also retain substantial neurogenic potential [99]. Their ability to expand and sustain neurogenic potential provides many advantages to be used in cell therapy; however, there have been difficulties in inducing differentiation of ES cells into striatal cells, which is especially important in HD. A report showed that mouse ES cells treated with retinoic acid could differentiate into neuronal cells that could integrate and survive in the QA-lesioned rat model of HD [100]. Another concern with the use of these cells is its potential for tumorigenicity, because even tiny numbers of undifferentiated cells at the time of transplantation may develop into tumors later on. To overcome these limitations of ES cells, research has shifted to using neural stem/precursor cells (NPCs). NPCs are a heterogeneous population of mitotically active, self-renewing, and multipotent cells, which can be isolated from the embryo [101]. Likewise, to use human neural precursors (hNP) derived from embryonic stem cells (hESCs) in HD cell therapy, hNP is required to differentiate into neuronal cells, especially MSN, in vivo. In vitro noggin priming can be an effective tool of hNP transplantation in HD treatment. Noggin-primed hNP showed survival, extensive migration, and differentiation into predominantly neuronal cells after transplantation in the QA-lesioned stratum of rats [102]. Recently, a protocol has been developed to obtain a high percentage of functional GABAergic neurons from mouse embryonic stem cells (mESCs) [103]. By combining an in vitro culture and an in vivo differentiation protocol, striatal progenitors derived from hESCs were shown to mature into DARPP-32-positive neurons in QA-lesioned rats [104]. Using neural precursor cells with elimination of undifferentiated cells, ESC-based regenerative approaches may be successful in treating HD patients. In addition to cell replacement potential, there is evidence that transplantation of NPCs may modulate inflammatory reactions through a “bystander” mechanism [105].

5.3. Non-neural stem cells

To avoid ethical problems, non-neural stem cells, such as adult stem cells or umbilical cord-derived cells, have been used as alternative cell sources for HD treatment. Because adult stem cells are relatively easy to harvest and autologous grafting is possible, there have been many studies using mesenchymal stem cells (MSCs) of the bone marrow [106-108] or adipose tissue [109, 110] in HD mouse models (Table 4). Although there is still debate about the possibility of cell fusion events rather than true transdifferentiation, these non-neural stem cells are known to have the capacity to differentiate into neurons after injection into the adult rodent host [111]. Intrastriatal MSC transplants reduced motor and pathological deficits in a 3-NP-lesioned rat and QA-lesioned mouse/rat HD models [106, 109, 112-115]. Genetically engineered stem cells that produce trophic factors could also be a cell source for cell therapy [116-118]. When genetically engineered bone marrow-derived MSCs overexpressing neurotrophic factors (NTFs), called NTF(+) cells, were transplanted into rat brains after QA injection, NTF(+) cells survived, maintained their NTF-secreting phenotype, and exhibited improved behavior and reduced striatal atrophy associated with QA lesions [119]. MSCs engineered to produce BDNF also improved behavioral performance and reduced striatal atrophy when transplanted in YAC128 mouse model of HD [120]. In addition, MSC-based studies take advantages of the property of MSCs to modulate the brain environment toward neuroprotection [116]. Injection of cell-free extracts of adipose-derived stem cells also demonstrates behavioral and pathological improvements of R6/2 models in terms of HD pathology [121].

Animal model Cells Histology Lesion volume Functional outcome Ref
Rat, QA Rat BM-MSCs Reduced striatal atrophy Improved striatal volume NA [106]
Rat, QA Human adipose MSCs Reduced striatal atrophy and apoptosis Decreased lesion volume Reduced Apo-M induced rotations [109]
Mouse, QA Human BM
Increased cell proliferation in striatum
Reduced apoptosis
Decreased lesion volume Improved rotarod performance
Extended survival
R6/2 mouse Human BM
Improved cell differentiation NA Improved survival [113]
Rat, QA Human BM
Reduced striatal atrophy
Increased level of NTFs
Decreased lesion volume Reduced motor dysfunction [114]
R6/2 mouse Human adipose MSCs Reduced Htt aggregates
Attenuated loss of striatal neurons
Improved striatal volume Improved rotarod
Reduced clasping
Improved survival
Rat, 3NP Rat BM-MSCs Increased striatal labeling in BDNF, collagen type-I and fibronectin Prevented 3NP-mediated ventricle enlargement Improved rotarod
Improved paw placement
Rat, QA Rat BM-MSCs Improved MSC migration to lesion Decreased lesion volume Regenerated striatal network
Reduced Apo-M induced rotations
Rat, QA Human BM-MSCs engineered to secret NTF Survived after 6 weeks
Sustained NTF secretion
Decreased lesion volume Reduced Apo-M induced rotations [119]
YAC 128 mouse Human adipose MSCs Reduced striatal atrophy Improved striatal volume Improved rotarod performance/ motor function [110]
Rat, QA Rat BM-MSCs NA NA Reduced Apo-M induced rotations
Improved beam walk and hang wire time
YAC 128 mouse BM-MSCs engineered to produce BDNF Reduced striatal atrophy Improved striatal volume Improved rotarod performance
Reduced hindlimb clasping
Mouse, QA hESC-derived GABA neurons and their progenitors Repopulated GABAergic cells, connecting with endogenous cells NA Improved rotarod, openfield, and tradscan performance [142]

Table 4.

Mesenchymal stem cell-based treatment of HD in preclinical rodent models

Apo-M=apomorphin; BDNF=brain-derived neurotrophic factor; BM-MSCs=bone-marrow-derived mesenchymal stem cells; hES=human embryonic stem cells; NA=not available; NTF=neurotrophic factor; QA=quinolinic acid; 3NP=3-nitropropionic acid

5.4. Induced Pluripotent Stem Cells (iPSCs)

Induced pluripotent stem cells (iPSCs) generated from somatic cells of patients can be used to model different human diseases, thereby enabling disease investigation and drug development [122]. Since the generation of iPSCs does not involve the destruction of human embryos, they can avoid the ethical issues related to the use of human ESCs [123]. In direct opposition to embryonic/fetal tissue-derived cells, patient-derived iPSCs can avoid immune rejection as well as ethical problems, and they can also serve as sources of transplantable cells in novel cell therapies [124]. Recently, non-integrating episomal vectors were introduced into the cell by electroporation, making transgene-free and virus-free iPSCs in a feeder-free environment [125]. There are controversial results regarding formation of mutant Htt proteins in HD patient-derived iPSCs (HD-iPSCs) [126, 127]. At least, HD-iPSCs can be differentiated into GABAergic striatal neurons and make significant behavioral recovery without aggregation formation at 12 weeks after transplantation [127]. Nevertheless, as HD is a genetic disorder, correction of HD mutations in HD-iPSCs is suggested to be an essential step before grafting to HD patients [122]. With the advent of new gene editing technologies using zinc-finger nuclease (ZFN), transcription activator-like effector nuclease (TALEN), and clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9, iPSCs that are derived from patients with gene mutations may still be a plausible cell source for transplantation [128, 129]. A nucleofection-based protocol adapted to single-cell dissociated feeder-free culture was established, and a reversal of HD phenotype and striatal differentiation of gene-corrected HD-iPSCs in vitro and in vivo are demonstrated [130]. If transgene-free reprogrammed iPSCs derived from patients could be made under good manufacturing practice (GMP), they may provide a suitable source for autologous transplantation in the future.


6. Results and problems of pre-clinical and clinical studies

6.1. Pre-clinical cell transplantation in Huntington’s Disease models

In view of HD pathology, it is important to rescue the vulnerable MSNs by slowing the inexorable loss of striatal neurons. To rescue the damaged striatum, embryonic striatal tissues were transplanted, and their survival, expression of a wide range of striatal markers, and the recovery of motor and cognitive functions were demonstrated by many tasks of evaluation both in HD toxin and genetic models (Tables 34) [131-133]. Although the extent of functional improvement was relatively modest in transgenic animal models, it was shown that the transplanted cells can connect with appropriate targets in the host brain [134] and function both electrophysiologically [135, 136] and neurochemically [137, 138], indicating that striatal grafts can yield a functional repair of striatal cell loss in HD [139]. The timing of cell transplantation should be also considered, as the pretreatment with human NSCs was shown to rescue the motor impairment and neuronal damage caused by systemic 3-NP administration [140]. When NSCs are transplanted after excitotoxin injection, the extent of neuronal recovery could be different according to the time interval between excitotoxin injection and NSC transplantation [94]. Another consideration on the cell transplantation is that transplanted cells should exhibit an MSN morphology, express MSN markers such as DARPP-32, and function in vivo to recover the lost functions [141]. Recently, hESC-derived DARPP32-expressing forebrain GABA neurons and their progenitors were implanted into QA-lesioned mice and they were connected with endogenous dopaminergic and glutamatergic neurons [142]. In the past two decades, clinical trials have been performed using human fetal striatal cells, and some reports have indicated clinical improvement with reduced motor dysfunction or slowed disease progression in some patients (Table 5). However, because human fetal tissue transplants inevitably raise ethical issues and risk of immune rejection, induced pluripotent stem cells (iPSCs) generated from skin fibroblasts of HD patients [122], can serve as an autologous cell source. HD-iPSCs could be differentiated into neural precursor cells and implantation of those cells in the striatum of QA-lesioned rats; behaviors improved significantly; and Htt aggregation was not formed at 12 weeks after transplantation [127]. In addition, various adult stem cells also demonstrated behavioral and pathological improvement after transplantations into toxin or transgenic rodent models (Table 4).

Donor tissue N Implant site Safety Efficacy Ref
VM or WGE 4 NA [B] No pathological or immunological response Not possible to determine [143]
E12-13 WGE 2 CN cavity No surgical incidents or subsequent SEs Slow progression [144]
E8-9 LLGE 7 pcPu [B] 1 death from cardiac arrest, 3 subdural hematomas Modest (NS) changes in motor tests at 12 months
Transplanted cells can survive and integrate anatomically over 10 years
E9-12 WGE 4 CN + pcPu [B] Safe; no serious SE Stabilization or improvement in some neurological indices
Prolonged graft survival with development of striatal-like structure
E7.5-9 WGE 5 2 CN + 3 Pu [B] Safe procedure Motor and electrophysiol improvements continue over 6 years [145, 155]
E8-10 LGE 14 1 CN + 4 Pu [B] Safe; no serious SEs Benefit motor, limited neuropsychogic tests [149, 150]
E8-12 WGE 4 2 CN + 4 Pu [U] Only SEs related to immunosuppression Safety only, efficacy not reported [153]
Porcine LGE 12 2 CN + 4 Pu [U] Safe; no serious SEs No change on TFC over 12 months [161]

Table 5.

Clinical trials in HD patients

CN = caudate nucleus; E = weeks of embryonic age; LLGE = lateral aspect of the lateral ganglionic eminence; NA=not available; NS=not significant; pcPU = postcommissural putamen; Pu = putamen; SEs = side effects; TFC=total functional capacity; WGE = whole ganglionic eminence; VM = ventral mesencephalon; [B] = bilateral implants; [U] = unilateral implants.

6.2. Clinical trials of cell transplantation in Huntington’s Disease

On the basis of the encouraging results from animal studies, clinical trials using fetal neural stem cells have been performed since 1990 (Table 5). In the early studies performed in Cuba, Czechoslovakia, and Mexico, implantation protocols and procedures were shown not to cause major complications or overt side effects [143, 144]. Afterward, extensive series of implants proved safety of the procedure in moderate stage of patients with functional and/or radiological improvement [145-148]. The first extensive series of fetal striatal tissue implantation was performed in Los Angeles, USA. The procedure was safe [149], and the results indicated motor and cognitive improvements in small numbers of patients [150]. Graft survival was identified by magnetic resonance spectroscopy [151]. Another study group in Tampa, Florida, USA, reported no overall improvement in motor function despite absence of immune rejection [146]. However, when patients with the procedure-dependent side effect (i.e., SDH) were excluded from the result analysis, motor scores were significantly improved after transplantation, and the postmortem brain analysis in one patient indicated healthy surviving grafts 18 months after transplantation and good differentiation into mature striatal-like tissue containing all striatal cell phenotypes [152]. Although three of the patients developed subdural hematoma after the surgery, this side effect could be avoided by careful selection of patients, i.e., patients without significant brain atrophy, for operation. Additional safety evaluation trial involving the United Kingdom arm of the European network for striatal transplantation (“NEST-UK”) resulted in no serious side effect related to the operation [153]. This group also suggested a comprehensive, logical yet pragmatic screening program for future neural transplantation [154]. Meanwhile, the efficacy of fetal striatal cell transplantation was shown in another study group, in which four patients with HD have the stabilization or improvement of motor indices after fetal neuroblast implantation, and the graft has survived and developed striatal-like structures in the host brain [148].

Another large-scale study has been going on in a multicenter trial in France (NCT00190450).

This study group is the first to undertake their trial in accordance with the standardized core assessment protocol for intracerebral transplantation in Huntington’s disease (CAPIT-HD), and detailed reports of transplantation in the first five patients have been published [145, 147, 155, 156]. In these series, three of the five patients showed motor and cognitive improvements two years after intracerebral fetal neural grafts, which were correlated with recovery of brain metabolic activity in grafted striatal areas and connected regions of the cerebral cortex, measured by fluorodeoxyglucose-positron emission tomography. Restoration of the lost sensory-evoked potentials is also noted. Furthermore, six years after transplantation, clinical improvements became plateaued and then fade off variably within 4–6 years while maintaining stable cognitive function. Cerebral metabolism has also deteriorated progressively, sparing the benefits in the frontal cortex and at the precise location of the grafts. This feature suggested that fetal neural transplantation provides a period of several years of improvement and stability, but not a permanent cure, and strategies of neuroprotection should be developed further [145]. Although it is still controversial, a recent study raised a possibility that the transplanted fetal striatal tissue can undergo disease-like neuronal degeneration after a decade of implantation [157]. Suboptimal long-term graft survival might be caused by the allograft immunoreactivity, microglial responses, and cell-to-cell neurotoxicity [158]. Recently, donor-specific anti-HLA antibodies were detected in six out of 16 patients with HD who received human fetal striatal transplants [159]. These results underline the importance of careful approach for developing cell-based therapy in HD.

Apart from using human fetal striatal tissue, there was a clinical trial using porcine-derived striatal xenografts. In this case, the transplanted patients were treated with cyclosporin or a monoclonal antibody directed against surface major histocompatibility complex I molecules [160]. However, the surviving grafts were not detectable on MRI, and the treatment gave rise to no functional benefit for the patients [161]. In the case of xenografts, fully effective immunosuppression strategies should be resolved.

In order to use neural stem cells for clinical trials, several aborted human fetal tissues are required. Whether derived from elective or spontaneous abortion, there are sensitive ethical and social issues associated with using human fetal tissues for transplantation. There are also difficulties with accurate staging and collection (subject to appropriate ethical approval) and storage of fetal tissues [162-164]. Therefore, in most cases, they would never meet the levels of standardization and quality control required.

The delivery of trophic factors by genetically modified cells into striatum of patient has become another therapeutic approach in HD. A variety of growth factors, including the neurotrophins, fibroblast growth factor (FGF), ciliary neurotrophic factor (CNTF), glia-derived neurotrophic factor (GDNF), and brain-derived neurotrophic factor (BDNF), have been found to promote survival of striatal neurons in culture [117, 118, 165]. Direct injection of various trophic factors incorporated into viral vectors has problems of standardization, regulation, and longevity of treatment. Instead, implantation of engineered cells to express the desired transgene has been suggested [166]. Intracerebral administration of a device formed by a semipermeable membrane encapsulating a BHK cell line engineered to synthesize CNTF has been tried. No sign of CNTF-induced toxicity was observed, while improvements in electrophysiological results were observed. However, depression was observed in three out of six HD patients, and heterogeneous cell survival in the device hindered further clinical trials [166, 167]. Recently, mesenchymal stem cell engineered to secrete BDNF has been suggested, due to its clinically applicable characteristics [116].


7. Future directions of Huntington’s Disease research and clinical applications

Therapeutic approaches using NSCs and other stem cell products for CNS diseases fall into two broad categories: (i) regenerative/cell replacement to promote host tissue repair mechanisms and/or to replace missing or damaged cells and (ii) therapeutic delivery of macromolecules (enzymes, cytokines, neurotrophins, drugs, etc.) for neuroprotection and/or stimulation of repair. However, because HD is a progressive neurodegenerative disease and stem cells might replace and protect only striatal neurons with limited capacity, stem cell therapy as means to stop disease progression might be insufficient [168]. As such, future directions of cell therapy in HD should move beyond the replacement of lost neurons. To date, clinical trials have been undertaken with fetal donor tissue in the striatum in HD. For therapeutic efficacy, reconstitution of a functional dynamic information-processing circuit without ectopic connections using transplanted stem cells is necessary. Another major challenge is to achieve controlled differentiation of embryonic stem cells or induced pluripotent stem cells into specific neuronal phenotypes, such as medium spiny neurons in the absence of aberrant growth or tumor formation. Furthermore, novel approaches to provide therapeutic molecules for neuroprotection should also be tried and verified.



This work was supported by a grant of the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science, and Technology (2012R1A1A2006827), Republic of Korea.


  1. 1. Andrade MA, Bork P: HEAT repeats in the Huntington’s disease protein. Nature genetics. 1995;11(2):115–6.
  2. 2. Sharp AH, Loev SJ, Schilling G, Li SH, Li XJ, Bao J, et al: Widespread expression of Huntington’s disease gene (IT15) protein product. Neuron. 1995;14(5):1065–74.
  3. 3. DiFiglia M, Sapp E, Chase K, Schwarz C, Meloni A, Young C, et al: Huntingtin is a cytoplasmic protein associated with vesicles in human and rat brain neurons. Neuron. 1995;14(5):1075–81.
  4. 4. De Rooij KE, Dorsman JC, Smoor MA, Den Dunnen JT, Van Ommen GJ: Subcellular localization of the Huntington’s disease gene product in cell lines by immunofluorescence and biochemical subcellular fractionation. Human Molecular Genetics. 1996;5(8):1093–9.
  5. 5. Savas JN, Ma B, Deinhardt K, Culver BP, Restituito S, Wu L, et al: A role for huntington disease protein in dendritic RNA granules. Journal of Biological Chemistry. 2010;285(17):13142–53.
  6. 6. Sugars KL, Rubinsztein DC: Transcriptional abnormalities in Huntington disease. Trends in Genetics. 2003;19(5):233–8.
  7. 7. Buckley NJ, Johnson R, Zuccato C, Bithell A, Cattaneo E: The role of REST in transcriptional and epigenetic dysregulation in Huntington’s disease. Neurobiology of Disease. 2010;39(1):28–39.
  8. 8. Cattaneo E, Zuccato C, Tartari M: Normal huntingtin function: an alternative approach to Huntington’s disease. Nature Reviews Neuroscience. 2005;6(12):919–30.
  9. 9. Zuccato C, Liber D, Ramos C, Tarditi A, Rigamonti D, Tartari M, et al: Progressive loss of BDNF in a mouse model of Huntington’s disease and rescue by BDNF delivery. Pharmacological Research. 2005;52(2):133–9.
  10. 10. Zeitlin S, Liu JP, Chapman DL, Papaioannou VE, Efstratiadis A: Increased apoptosis and early embryonic lethality in mice nullizygous for the Huntington’s disease gene homologue. Nature Genetics. 1995;11(2):155–63.
  11. 11. Nagai Y, Inui T, Popiel HA, Fujikake N, Hasegawa K, Urade Y, et al: A toxic monomeric conformer of the polyglutamine protein. Nature Structural and Molecular Biology. 2007;14(4):332–40.
  12. 12. Zuccato CMV, Cattaneo E: Molecular mechanisms and potential therapeutic targets in Huntington’s disease. Physiological Reviews. 2010;90:905–81.
  13. 13. Ross CA, Tabrizi SJ: Huntington’s disease: from molecular pathogenesis to clinical treatment. Lancet Neurology. 2011;10(1):83–98.
  14. 14. Leegwater-Kim J, Cha JH: The paradigm of Huntington’s disease: therapeutic opportunities in neurodegeneration. NeuroRx: The Journal of the American Society for Experimental NeuroTherapeutics. 2004;1(1):128–38.
  15. 15. Shao J, Diamond MI: Polyglutamine diseases: emerging concepts in pathogenesis and therapy. Human Molecular Genetics. 2007;16(Spec No. 2):R115–23.
  16. 16. Tobin AJ, Signer ER: Huntington’s disease: the challenge for cell biologists. Trends in Cell Biology. 2000;10(12):531–6.
  17. 17. Pringsheim T, Wiltshire K, Day L, Dykeman J, Steeves T, Jette N: The incidence and prevalence of Huntington’s disease: a systematic review and meta-analysis. Movement Disorders. 2012;27(9):1083–91.
  18. 18. Gusella JF, MacDonald ME, Lee JM: Genetic modifiers of Huntington’s disease. Movement Disorders. 2014;29(11):1359–65.
  19. 19. Langbehn DR, Brinkman RR, Falush D, Paulsen JS, Hayden MR, International Huntington’s Disease Collaborative G: A new model for prediction of the age of onset and penetrance for Huntington’s disease based on CAG length. Clinical Genetics. 2004;65(4):267–77.
  20. 20. Wexler NS, Lorimer J, Porter J, Gomez F, Moskowitz C, Shackell E, et al: Venezuelan kindreds reveal that genetic and environmental factors modulate Huntington’s disease age of onset. Proceedings of the National Academy of Sciences of the United States of America. 2004;101(10):3498–503.
  21. 21. Lee JM, Ramos EM, Lee JH, Gillis T, Mysore JS, Hayden MR, et al: CAG repeat expansion in Huntington disease determines age at onset in a fully dominant fashion. Neurology. 2012;78:690–5.
  22. 22. Huntington G: On chorea. Medical and Surgical Reporter. 1872;26:317–21.
  23. 23. van der Burg JM, Bjorkqvist M, Brundin P: Beyond the brain: widespread pathology in Huntington’s disease. Lancet Neurology. 2009;8(8):765–74.
  24. 24. Halliday GM, McRitchie DA, Macdonald V, Double KL, Trent RJ, McCusker E: Regional specificity of brain atrophy in Huntington’s disease. Experimental Neurology. 1998;154(2):663–72.
  25. 25. Subramaniam S, Sixt KM, Barrow R, Snyder SH: Rhes, a striatal specific protein, mediates mutant-huntingtin cytotoxicity. Science. 2009;324(5932):1327–30.
  26. 26. Rockabrand E, Slepko N, Pantalone A, Nukala VN, Kazantsev A, Marsh JL, et al: The first 17 amino acids of Huntingtin modulate its sub-cellular localization, aggregation and effects on calcium homeostasis. Human Molecular Genetics. 2007;16(1):61–77.
  27. 27. Gu X, Greiner ER, Mishra R, Kodali R, Osmand A, Finkbeiner S, et al: Serines 13 and 16 are critical determinants of full-length human mutant huntingtin induced disease pathogenesis in HD mice. Neuron. 2009;64(6):828–40.
  28. 28. Yanai A, Huang K, Kang R, Singaraja RR, Arstikaitis P, Gan L, et al: Palmitoylation of huntingtin by HIP14 is essential for its trafficking and function. Nature Neuroscience. 2006;9(6):824–31.
  29. 29. Cowan CM, Raymond LA: Selective neuronal degeneration in Huntington’s disease. Current Topics in Developmental Biology. 2006;75:25–71.
  30. 30. Shin JY, Fang ZH, Yu ZX, Wang CE, Li SH, Li XJ: Expression of mutant huntingtin in glial cells contributes to neuronal excitotoxicity. Journal of Cell Biology. 2005;171(6):1001–12.
  31. 31. Juopperi TA, Kim WR, Chiang CH, Yu H, Margolis RL, Ross CA, et al: Astrocytes generated from patient induced pluripotent stem cells recapitulate features of Huntington’s disease patient cells. Molecular Brain. 2012;5(1):17.
  32. 32. Bradford J, Shin JY, Roberts M, Wang CE, Li XJ, Li S: Expression of mutant huntingtin in mouse brain astrocytes causes age-dependent neurological symptoms. Proceedings of the National Academy of Sciences of the United States of America. 2009;106(52):22480–5.
  33. 33. Pavese N, Gerhard A, Tai YF, Ho AK, Turkheimer F, Barker RA, et al: Microglial activation correlates with severity in Huntington disease: a clinical and PET study. Neurology. 2006;66(11):1638–43.
  34. 34. Tai YF, Pavese N, Gerhard A, Tabrizi SJ, Barker RA, Brooks DJ, et al: Microglial activation in presymptomatic Huntington’s disease gene carriers. Brain. 2007;130(Pt 7):1759–66.
  35. 35. Kenney C, Jankovic J: Tetrabenazine in the treatment of hyperkinetic movement disorders. Expert Review of Neurotherapeutics. 2006;6(1):7–17.
  36. 36. Fernandez HH, Friedman JH, Grace J, Beason-Hazen S: Donepezil for Huntington’s disease. Movement Disorders. 2000;15(1):173–6.
  37. 37. de Tommaso M, Difruscolo O, Sciruicchio V, Specchio N, Livrea P: Two years’ follow-up of rivastigmine treatment in Huntington disease. Clinical Neuropharmacology. 2007;30(1):43–6.
  38. 38. Nance MA, Sanders G: Characteristics of individuals with Huntington disease in long-term care. Movement Disorders. 1996;11(5):542–8.
  39. 39. Myers RH, Sax DS, Koroshetz WJ, Mastromauro C, Cupples LA, Kiely DK, et al: Factors associated with slow progression in Huntington’s disease. Archives of Neurology. 1991;48(8):800–4.
  40. 40. Benn CL, Luthi-Carter R, Kuhn A, Sadri-Vakili G, Blankson KL, Dalai SC, et al: Environmental enrichment reduces neuronal intranuclear inclusion load but has no effect on messenger RNA expression in a mouse model of Huntington disease. Journal of Neuropathology and Experimental Neurology. 2010;69(8):817–27.
  41. 41. van Dellen A, Blakemore C, Deacon R, York D, Hannan AJ: Delaying the onset of Huntington’s in mice. Nature. 2000;404(6779):721–2.
  42. 42. Landwehrmeyer GB, Dubois B, de Yebenes JG, Kremer B, Gaus W, Kraus PH, et al: Riluzole in Huntington’s disease: a 3-year, randomized controlled study. Annals of Neurology. 2007;62(3):262–72.
  43. 43. Peyser CE, Folstein M, Chase GA, Starkstein S, Brandt J, Cockrell JR, et al: Trial of d-alpha-tocopherol in Huntington’s disease American Journal of Psychiatry. 1995;152(12):1771–5.
  44. 44. Huntington Study Group: A randomized, placebo-controlled trial of coenzyme Q10 and remacemide in Huntington’s disease. Neurology. 2001;57(3):397–404.
  45. 45. Huntington Study Group: A futility study of minocycline in Huntington’s disease. Movement Disorders. 2010;25(13):2219–24.
  46. 46. Mestre T, Ferreira J, Coelho MM, Rosa M, Sampaio C: Therapeutic interventions for disease progression in Huntington’s disease. The Cochrane Database of Systematic Reviews. 2009(3):CD006455.
  47. 47. Wild EJ, Tabrizi SJ: Targets for future clinical trials in Huntington’s disease: what’s in the pipeline? Movement Disorders. 2014;29(11):1434–45.
  48. 48. Ferrante RJ: Mouse models of Huntington’s disease and methodological considerations for therapeutic trials. Biochimica et Biophysica Acta. 2009;1792(6):506–20.
  49. 49. Schwarcz R, Coyle JT: Striatal lesions with kainic acid: neurochemical characteristics. Brain Research. 1977;127(2):235–49.
  50. 50. Schwarcz R, Whetsell WO, Jr., Mangano RM: Quinolinic acid: an endogenous metabolite that produces axon-sparing lesions in rat brain. Science. 1983;219(4582):316–8.
  51. 51. Beal MF, Brouillet E, Jenkins BG, Ferrante RJ, Kowall NW, Miller JM, et al: Neurochemical and histologic characterization of striatal excitotoxic lesions produced by the mitochondrial toxin 3-nitropropionic acid. Journal of Neuroscience. 1993;13(10):4181–92.
  52. 52. Brouillet E, Conde F, Beal MF, Hantraye P: Replicating Huntington’s disease phenotype in experimental animals. Progress in Neurobiology. 1999;59(5):427–68.
  53. 53. Dunnett SB, Rosser AE: Cell therapy in Huntington’s disease. NeuroRx. 2004;1(4):394–405.
  54. 54. Cepeda C, Cummings DM, Andre VM, Holley SM, Levine MS: Genetic mouse models of Huntington’s disease: focus on electrophysiological mechanisms. ASN Neuro. 2010;2(2):e00033.
  55. 55. Pouladi MA, Morton AJ, Hayden MR: Choosing an animal model for the study of Huntington’s disease. Nature Reviews Neuroscience. 2013;14(10):708–21.
  56. 56. Mangiarini L, Sathasivam K, Seller M, Cozens B, Harper A, Hetherington C, et al: Exon 1 of the HD gene with an expanded CAG repeat is sufficient to cause a progressive neurological phenotype in transgenic mice. Cell. 1996;87(3):493–506.
  57. 57. Naver B, Stub C, Moller M, Fenger K, Hansen AK, Hasholt L, et al: Molecular and behavioral analysis of the R6/1 Huntington’s disease transgenic mouse. Neuroscience. 2003;122(4):1049–57.
  58. 58. Laforet GA, Sapp E, Chase K, McIntyre C, Boyce FM, Campbell M, et al: Changes in cortical and striatal neurons predict behavioral and electrophysiological abnormalities in a transgenic murine model of Huntington’s disease. Journal of Neuroscience. 2001;21(23):9112–23.
  59. 59. Schilling G, Becher MW, Sharp AH, Jinnah HA, Duan K, Kotzuk JA, et al: Intranuclear inclusions and neuritic aggregates in transgenic mice expressing a mutant N-terminal fragment of huntingtin. Human Molecular Genetics. 1999;8(3):397–407.
  60. 60. von Horsten S, Schmitt I, Nguyen HP, Holzmann C, Schmidt T, Walther T, et al: Transgenic rat model of Huntington’s disease. Human Molecular Genetics. 2003;12(6):617–24.
  61. 61. Hodgson JG, Smith DJ, McCutcheon K, Koide HB, Nishiyama K, Dinulos MB, et al: Human huntingtin derived from YAC transgenes compensates for loss of murine huntingtin by rescue of the embryonic lethal phenotype. Human Molecular Genetics. 1996;5(12):1875–85.
  62. 62. Slow EJ, van Raamsdonk J, Rogers D, Coleman SH, Graham RK, Deng Y, et al: Selective striatal neuronal loss in a YAC128 mouse model of Huntington disease. Human Molecular Genetics. 2003;12(13):1555–67.
  63. 63. Reddy PH, Williams M, Charles V, Garrett L, Pike-Buchanan L, Whetsell WO, Jr., et al: Behavioural abnormalities and selective neuronal loss in HD transgenic mice expressing mutated full-length HD cDNA. Nature Genetics. 1998;20(2):198–202.
  64. 64. Gray M, Shirasaki DI, Cepeda C, Andre VM, Wilburn B, Lu XH, et al: Full-length human mutant huntingtin with a stable polyglutamine repeat can elicit progressive and selective neuropathogenesis in BACHD mice. Journal of Neuroscience. 2008;28(24):6182–95.
  65. 65. Southwell AL, Warby SC, Carroll JB, Doty CN, Skotte NH, Zhang W, et al: A fully humanized transgenic mouse model of Huntington disease. Human Molecular Genetics. 2013;22(1):18–34.
  66. 66. Wheeler VC, Auerbach W, White JK, Srinidhi J, Auerbach A, Ryan A, et al: Length-dependent gametic CAG repeat instability in the Huntington’s disease knock-in mouse. Human Molecular Genetics. 1999;8(1):115–22.
  67. 67. Wheeler VC, Gutekunst CA, Vrbanac V, Lebel LA, Schilling G, Hersch S, et al: Early phenotypes that presage late-onset neurodegenerative disease allow testing of modifiers in Hdh CAG knock-in mice. Human Molecular Genetics. 2002;11(6):633–40.
  68. 68. Wheeler VC, White JK, Gutekunst CA, Vrbanac V, Weaver M, Li XJ, et al: Long glutamine tracts cause nuclear localization of a novel form of huntingtin in medium spiny striatal neurons in HdhQ92 and HdhQ111 knock-in mice. Human Molecular Genetics. 2000;9(4):503–13.
  69. 69. Menalled LB, Sison JD, Dragatsis I, Zeitlin S, Chesselet MF: Time course of early motor and neuropathological anomalies in a knock-in mouse model of Huntington’s disease with 140 CAG repeats. Journal of Comparative Neurology. 2003;465(1):11–26.
  70. 70. Lin CH, Tallaksen-Greene S, Chien WM, Cearley JA, Jackson WS, Crouse AB, et al: Neurological abnormalities in a knock-in mouse model of Huntington’s disease. Human Molecular Genetics. 2001;10(2):137–44.
  71. 71. Tabrizi SJ, Workman J, Hart PE, Mangiarini L, Mahal A, Bates G, et al: Mitochondrial dysfunction and free radical damage in the Huntington R6/2 transgenic mouse. Annals of Neurology. 2000;47(1):80–6.
  72. 72. Cha JH, Kosinski CM, Kerner JA, Alsdorf SA, Mangiarini L, Davies SW, et al: Altered brain neurotransmitter receptors in transgenic mice expressing a portion of an abnormal human huntington disease gene. Proceedings of the National Academy of Sciences of the United States of America. 1998;95(11):6480–5.
  73. 73. Murphy KP, Carter RJ, Lione LA, Mangiarini L, Mahal A, Bates GP, et al: Abnormal synaptic plasticity and impaired spatial cognition in mice transgenic for exon 1 of the human Huntington’s disease mutation. Journal of Neuroscience. 2000;20(13):5115–23.
  74. 74. Cummings DM, Milnerwood AJ, Dallerac GM, Vatsavayai SC, Hirst MC, Murphy KP: Abnormal cortical synaptic plasticity in a mouse model of Huntington’s disease. Brain Research Bulletin. 2007;72(2–3):103–7.
  75. 75. Menalled LB, Chesselet MF: Mouse models of Huntington’s disease. Trends in Pharmacological Sciences. 2002;23(1):32–9.
  76. 76. Hodgson JG, Agopyan N, Gutekunst CA, Leavitt BR, LePiane F, Singaraja R, et al: A YAC mouse model for Huntington’s disease with full-length mutant huntingtin, cytoplasmic toxicity, and selective striatal neurodegeneration. Neuron. 1999;23(1):181–92.
  77. 77. Van Raamsdonk JM, Warby SC, Hayden MR: Selective degeneration in YAC mouse models of Huntington disease. Brain Research Bulletin. 2007;72(2–3):124–31.
  78. 78. Yang XW, Gray M: Mouse Models for Validating Preclinical Candidates for Huntington’s Disease. In: Lo DC, Hughes RE, editors. Neurobiology of Huntington’s Disease: Applications to Drug Discovery. Frontiers in Neuroscience. Boca Raton (FL): CRC Press; 2011. Chapter 7. Available from:
  79. 79. Burns LH, Pakzaban P, Deacon TW, Brownell AL, Tatter SB, Jenkins BG, et al: Selective putaminal excitotoxic lesions in non-human primates model the movement disorder of Huntington disease. Neuroscience. 1995;64(4):1007–17.
  80. 80. Yang SH, Cheng PH, Banta H, Piotrowska-Nitsche K, Yang JJ, Cheng EC, et al: Towards a transgenic model of Huntington’s disease in a non-human primate. Nature. 2008;453(7197):921–4.
  81. 81. Yang D, Wang CE, Zhao B, Li W, Ouyang Z, Liu Z, et al: Expression of Huntington’s disease protein results in apoptotic neurons in the brains of cloned transgenic pigs. Human Molecular Genetics. 2010;19(20):3983–94.
  82. 82. Jacobsen JC, Bawden CS, Rudiger SR, McLaughlan CJ, Reid SJ, Waldvogel HJ, et al: An ovine transgenic Huntington’s disease model. Human Molecular Genetics. 2010;19(10):1873–82.
  83. 83. Kocerha J, Liu Y, Willoughby D, Chidamparam K, Benito J, Nelson K, et al: Longitudinal transcriptomic dysregulation in the peripheral blood of transgenic Huntington’s disease monkeys. BMC Neuroscience. 2013;14:88.
  84. 84. Huntington’s Disease Sheep Collaborative Research Group, Reid SJ, Patassini S, Handley RR, Rudiger SR, McLaughlan CJ, et al: Further molecular characterisation of the OVT73 transgenic sheep model of Huntington’s disease identifies cortical aggregates. Journal of Huntington’s Disease. 2013;2(3):279–95.
  85. 85. Baxa M, Hruska-Plochan M, Juhas S, Vodicka P, Pavlok A, Juhasova J, et al: A transgenic minipig model of Huntington’s disease. Journal of Huntington’s Disease. 2013;2(1):47–68.
  86. 86. Lindvall O, Kokaia Z, Martinez-Serrano A: Stem cell therapy for human neurodegenerative disorders-how to make it work. Nature Medicine. 2004;10 Suppl:S42–50.
  87. 87. Bjorklund A, Lindvall O: Cell replacement therapies for central nervous system disorders. Nature Neuroscience. 2000;3(6):537–44.
  88. 88. Dunnett SB, Rosser AE: Stem cell transplantation for Huntington’s disease. Experimental Neurology. 2007;203(2):279–92.
  89. 89. Armstrong RJ, Svendsen CN: Neural stem cells: from cell biology to cell replacement. Cell Transplantation. 2000;9(2):139–52.
  90. 90. 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 Transplantation. 2000;9(1):55–64.
  91. 91. Lillien L: Neural progenitors and stem cells: mechanisms of progenitor heterogeneity. Current Opinion in Neurobiology. 1998;8(1):37–44.
  92. 92. McBride JL, Behrstock SP, Chen EY, Jakel RJ, Siegel I, Svendsen CN, et al: Human neural stem cell transplants improve motor function in a rat model of Huntington’s disease. Journal of Comparative Neurology. 2004;475(2):211–9.
  93. 93. Lee ST, Chu K, Park JE, Lee K, Kang L, Kim SU, et al: Intravenous administration of human neural stem cells induces functional recovery in Huntington’s disease rat model. Neuroscience Research. 2005;52(3):243–9.
  94. 94. Johann V, Schiefer J, Sass C, Mey J, Brook G, Kruttgen A, et al: Time of transplantation and cell preparation determine neural stem cell survival in a mouse model of Huntington’s disease. Experimental Brain Research. 2007;177(4):458–70.
  95. 95. Kordower JH, Chen EY, Winkler C, Fricker R, Charles V, Messing A, 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. Journal of Comparative Neurology. 1997;387(1):96–113.
  96. 96. Chung S, Shin BS, Hwang M, Lardaro T, Kang UJ, Isacson O, et al: Neural precursors derived from embryonic stem cells, but not those from fetal ventral mesencephalon, maintain the potential to differentiate into dopaminergic neurons after expansion in vitro. Stem Cells. 2006;24(6):1583–93.
  97. 97. El Akabawy G, Rattray I, Johansson SM, Gale R, Bates G, Modo M: Implantation of undifferentiated and predifferentiated human neural stem cells in the R6/2 transgenic mouse model of Huntington’s disease. BMC Neuroscience. 2012;13(1):97.
  98. 98. Reubinoff BE, Pera MF, Fong CY, Trounson A, Bongso A: Embryonic stem cell lines from human blastocysts: somatic differentiation in vitro. Nature Biotechnology. 2000;18(4):399–404.
  99. 99. Zhang SC, Wernig M, Duncan ID, Brustle O, Thomson JA: In vitro differentiation of transplantable neural precursors from human embryonic stem cells. Nature Biotechnology. 2001;19(12):1129–33.
  100. 100. Dinsmore J, Ratliff J, Deacon T, Pakzaban P, Jacoby D, Galpern W, et al: Embryonic stem cells differentiated in vitro as a novel source of cells for transplantation. Cell transplantation. 1996;5(2):131–43.
  101. 101. Gage FH. Mammalian neural stem cells. Science. 2000;287(5457):1433–8.
  102. 102. Vazey EM, Dottori M, Jamshidi P, Tomas D, Pera MF, Horne M, et al: Comparison of transplant efficiency between spontaneously derived and noggin-primed human embryonic stem cell neural precursors in the quinolinic acid rat model of Huntington’s disease. Cell Transplantation. 2010;19(8):1055–62.
  103. 103. 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 Reviews. 2012;8(2):513–31.
  104. 104. 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. Proceedings of the National Academy of Sciences of the United States of America. 2008;105(43):16707–12.
  105. 105. Martino G, Pluchino S: The therapeutic potential of neural stem cells. Nature Reviews Neuroscience. 2006;7(5):395–406.
  106. 106. Amin EM, Reza BA, Morteza BR, Maryam MM, Ali M, Zeinab N: Microanatomical evidences for potential of mesenchymal stem cells in amelioration of striatal degeneration. Neurological Research. 2008;30(10):1086–90.
  107. 107. Sadan O, Shemesh N, Barzilay R, Bahat-Stromza M, Melamed E, Cohen Y, et al: Migration of neurotrophic factors-secreting mesenchymal stem cells toward a quinolinic acid lesion as viewed by magnetic resonance imaging. Stem Cells. 2008;26(10):2542–51.
  108. 108. Edalatmanesh MA, Matin MM, Neshati Z, Bahrami AR, Kheirabadi M: Systemic transplantation of mesenchymal stem cells can reduce cognitive and motor deficits in rats with unilateral lesions of the neostriatum. Neurological Research. 2010;32(2):166–72.
  109. 109. Lee ST, Chu K, Jung KH, Im WS, Park JE, Lim HC, et al: Slowed progression in models of Huntington disease by adipose stem cell transplantation. Annals of Neurology. 2009;66(5):671–81.
  110. 110. Im W, Lee ST, Park JE, Oh HJ, Shim J, Lim J, et al: Transplantation of patient-derived adipose stem cells in YAC128 Huntington’s disease transgenic mice. PLoS Curr. 2010;2.
  111. 111. Long Y, Yang KY: Bone marrow derived cells for brain repair: recent findings and current controversies. Current Molecular Medicine. 2003;3(8):719–25.
  112. 112. Rossignol J, Boyer C, Leveque X, Fink KD, Thinard R, Blanchard F, et al: Mesenchymal stem cell transplantation and DMEM administration in a 3NP rat model of Huntington’s disease: morphological and behavioral outcomes. Behavioural Brain Research. 2011;217(2):369–78.
  113. 113. Lin YT, Chern Y, Shen CK, Wen HL, Chang YC, Li H, et al: Human mesenchymal stem cells prolong survival and ameliorate motor deficit through trophic support in Huntington’s disease mouse models. PloS One. 2011;6(8):e22924.
  114. 114. 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. Neurological Research. 2011;33(3):331–7.
  115. 115. Moraes L, Vasconcelos-dos-Santos A, Santana FC, Godoy MA, Rosado-de-Castro PH, Jasmin, et al: Neuroprotective effects and magnetic resonance imaging of mesenchymal stem cells labeled with SPION in a rat model of Huntington’s disease. Stem Cell Research. 2012;9(2):143–55.
  116. 116. Olson SD, Pollock K, Kambal A, Cary W, Mitchell GM, Tempkin J, et al: Genetically engineered mesenchymal stem cells as a proposed therapeutic for Huntington’s disease. Molecular Neurobiology. 2012;45(1):87–98.
  117. 117. Ventimiglia R, Mather PE, Jones BE, Lindsay RM: The neurotrophins BDNF, NT-3 and NT-4/5 promote survival and morphological and biochemical differentiation of striatal neurons in vitro. European journal of Neuroscience. 1995;7(2):213–22.
  118. 118. Nakao N, Odin P, Lindvall O, Brundin P: Differential trophic effects of basic fibroblast growth factor, insulin-like growth factor-1, and neurotrophin-3 on striatal neurons in culture. Experimental Neurology. 1996;138(1):144–57.
  119. 119. Sadan O, Shemesh N, Barzilay R, Dadon-Nahum M, Blumenfeld-Katzir T, Assaf Y, et al: Mesenchymal stem cells induced to secrete neurotrophic factors attenuate quinolinic acid toxicity: a potential therapy for Huntington’s disease. Experimental Neurology. 2012;234(2):417–27.
  120. 120. Dey ND, Bombard MC, Roland BP, Davidson S, Lu M, Rossignol J, et al: Genetically engineered mesenchymal stem cells reduce behavioral deficits in the YAC 128 mouse model of Huntington’s disease. Behavioural Brain Research. 2010;214(2):193–200.
  121. 121. Im W, Ban J, Lim J, Lee M, Lee ST, Chu K, et al: Extracts of adipose derived stem cells slows progression in the R6/2 model of Huntington’s disease. PloS One. 2013;8(4):e59438.
  122. 122. Park IH, Arora N, Huo H, Maherali N, Ahfeldt T, Shimamura A, et al: Disease-specific induced pluripotent stem cells. Cell. 2008;134(5):877–86.
  123. 123. Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, et al: Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell. 2007;131(5):861–72.
  124. 124. Perrier A, Peschanski M: How can human pluripotent stem cells help decipher and cure Huntington’s disease? Cell Stem Cell. 2012;11(2):153–61.
  125. 125. Yu J, Hu K, Smuga-Otto K, Tian S, Stewart R, Slukvin, II, et al: Human induced pluripotent stem cells free of vector and transgene sequences. Science. 2009;324(5928):797–801.
  126. 126. HD iPSC Consortium: Induced pluripotent stem cells from patients with Huntington’s disease show CAG-repeat-expansion-associated phenotypes. Cell Stem Cell. 2012;11(2):264–78.
  127. 127. Jeon I, Lee N, Li JY, Park IH, Park KS, Moon J, et al: Neuronal properties, in vivo effects, and pathology of a Huntington’s disease patient-derived induced pluripotent stem cells. Stem Cells. 2012;30(9):2054–62.
  128. 128. Hockemeyer D, Wang H, Kiani S, Lai CS, Gao Q, Cassady JP, et al: Genetic engineering of human pluripotent cells using TALE nucleases. Nature Biotechnology. 2011;29(8):731–4.
  129. 129. Smith C, Abalde-Atristain L, He C, Brodsky BR, Braunstein EM, Chaudhari P, et al: Efficient and allele-specific genome editing of disease loci in human iPSCs. Molecular Therapy. 2014. doi: 10.1038/mt.2014.226.
  130. 130. An MC, Zhang N, Scott G, Montoro D, Wittkop T, Mooney S, et al: Genetic correction of Huntington’s disease phenotypes in induced pluripotent stem cells. Cell Stem Cell. 2012;11(2):253–63.
  131. 131. Dobrossy MD, Dunnett SB: Striatal grafts alleviate deficits in response execution in a lateralised reaction time task. Brain Research Bulletin. 1998;47(6):585–93.
  132. 132. Dunnett SB, Carter RJ, Watts C, Torres EM, Mahal A, Mangiarini L, et al: Striatal transplantation in a transgenic mouse model of Huntington’s disease. Experimental Neurology. 1998;154(1):31–40.
  133. 133. van Dellen A, Deacon R, York D, Blakemore C, Hannan AJ: Anterior cingulate cortical transplantation in transgenic Huntington’s disease mice. Brain Research Bulletin. 2001;56(3–4):313–8.
  134. 134. Wictorin K: Anatomy and connectivity of intrastriatal striatal transplants. Progress in Neurobiology. 1992;38(6):611–39.
  135. 135. Xu ZC, Wilson CJ, Emson PC: Synaptic potentials evoked in spiny neurons in rat neostriatal grafts by cortical and thalamic stimulation. Journal of Neurophysiology. 1991;65(3):477–93.
  136. 136. Nakao N, Ogura M, Nakai K, Itakura T: Embryonic striatal grafts restore neuronal activity of the globus pallidus in a rodent model of Huntington’s disease. Neuroscience. 1999;88(2):469–77.
  137. 137. Sirinathsinghji DJ, Heavens RP, Torres EM, Dunnett SB: Cholecystokinin-dependent regulation of host dopamine inputs to striatal grafts. Neuroscience. 1993;53(3):651–63.
  138. 138. Campbell K, Kalen P, Wictorin K, Lundberg C, Mandel RJ, Bjorklund A: Characterization of GABA release from intrastriatal striatal transplants: dependence on host-derived afferents. Neuroscience. 1993;53(2):403–15.
  139. 139. Sirinathsinghji DJ, Dunnett SB, Isacson O, Clarke DJ, Kendrick K, Bjorklund A: Striatal grafts in rats with unilateral neostriatal lesions – II. In vivo monitoring of GABA release in globus pallidus and substantia nigra. Neuroscience. 1988;24(3):803–11.
  140. 140. Ryu JK, Kim J, Cho SJ, Hatori K, Nagai A, Choi HB, et al: Proactive transplantation of human neural stem cells prevents degeneration of striatal neurons in a rat model of Huntington disease. Neurobiology of Disease. 2004;16(1):68–77.
  141. 141. Kelly CM, Dunnett SB, Rosser AE. Medium spiny neurons for transplantation in Huntington’s disease. Biochemical Society Transactions. 2009;37(Pt 1):323–8.
  142. 142. Ma L, Hu B, Liu Y, Vermilyea SC, Liu H, Gao L, et al: Human embryonic stem cell-derived GABA neurons correct locomotion deficits in quinolinic acid-lesioned mice. Cell Stem Cell. 2012;10(4):455–64.
  143. 143. Sramka M, Rattaj M, Molina H, Vojtassak J, Belan V, Ruzicky E: Stereotactic technique and pathophysiological mechanisms of neurotransplantation in Huntington’s chorea. Stereotactic and Functional Neurosurgery. 1992;58(1–4):79–83.
  144. 144. Madrazo I, Franco-Bourland RE, Castrejon H, Cuevas C, Ostrosky-Solis F: Fetal striatal homotransplantation for Huntington’s disease: first two case reports. Neurological Research. 1995;17(4):312–5.
  145. 145. Bachoud-Levi AC, Gaura V, Brugieres P, Lefaucheur JP, Boisse MF, Maison 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 Neurology. 2006;5(4):303–9.
  146. 146. Hauser RA, Furtado S, Cimino CR, Delgado H, Eichler S, Schwartz S, et al: Bilateral human fetal striatal transplantation in Huntington’s disease. Neurology. 2002;58(5):687–95.
  147. 147. Gaura V, Bachoud-Levi AC, Ribeiro MJ, Nguyen JP, Frouin V, Baudic S, et al: Striatal neural grafting improves cortical metabolism in Huntington’s disease patients. Brain. 2004;127(Pt 1):65–72.
  148. 148. Gallina P, Paganini M, Lombardini L, Mascalchi M, Porfirio B, Gadda D, et al: Human striatal neuroblasts develop and build a striatal-like structure into the brain of Huntington’s disease patients after transplantation. Experimental Neurology. 2010;222(1):30–41.
  149. 149. Kopyov OV, Jacques S, Lieberman A, Duma CM, Eagle KS: Safety of intrastriatal neurotransplantation for Huntington’s disease patients. Experimental Neurology. 1998;149(1):97–108.
  150. 150. Philpott LM, Kopyov OV, Lee AJ, Jacques S, Duma CM, Caine S, et al: Neuropsychological functioning following fetal striatal transplantation in Huntington’s chorea: three case presentations. Cell Transplantation. 1997;6(3):203–12.
  151. 151. Ross BD, Hoang TQ, Bluml S, Dubowitz D, Kopyov OV, Jacques DB, et al: In vivo magnetic resonance spectroscopy of human fetal neural transplants. NMR in Biomedicine. 1999;12(4):221–36.
  152. 152. Freeman TB, Cicchetti F, Hauser RA, Deacon TW, Li XJ, Hersch SM, et al: Transplanted fetal striatum in Huntington’s disease: phenotypic development and lack of pathology. Proceedings of the National Academy of Sciences of the United States of America. 2000;97(25):13877–82.
  153. 153. Rosser AE, Barker RA, Harrower T, Watts C, Farrington M, Ho AK, et al: Unilateral transplantation of human primary fetal tissue in four patients with Huntington’s disease: NEST-UK safety report ISRCTN no 36485475. Journal of Neurology, Neurosurgery, and Psychiatry. 2002;73(6):678–85.
  154. 154. Farrington M, Wreghitt TG, Lever AM, Dunnett SB, Rosser AE, Barker RA: Neural transplantation in Huntington’s disease: the NEST-UK donor tissue microbiological screening program and review of the literature. Cell Transplantation. 2006;15(4):279–94.
  155. 155. Bachoud-Levi A, Bourdet C, Brugieres P, Nguyen JP, Grandmougin T, Haddad B, et al: Safety and tolerability assessment of intrastriatal neural allografts in five patients with Huntington’s disease. Experimental Neurology. 2000;161(1):194–202.
  156. 156. Bachoud-Levi AC, Remy P, Nguyen JP, Brugieres P, Lefaucheur JP, Bourdet C, et al: Motor and cognitive improvements in patients with Huntington’s disease after neural transplantation. Lancet. 2000;356(9246):1975–9.
  157. 157. Cicchetti F, Saporta S, Hauser RA, Parent M, Saint-Pierre M, Sanberg PR, et al: Neural transplants in patients with Huntington’s disease undergo disease-like neuronal degeneration. Proceedings of the National Academy of Sciences of the United States of America. 2009;106(30):12483–8.
  158. 158. Cicchetti F, Soulet D, Freeman TB: Neuronal degeneration in striatal transplants and Huntington’s disease: potential mechanisms and clinical implications. Brain. 2011;134(Pt 3):641–52.
  159. 159. Porfirio B, Paganini M, Mazzanti B, Bagnoli S, Bucciantini S, Ghelli E, et al: Donor-specific anti-HLA antibodies in Huntington’s disease recipients of human fetal striatal grafts. Cell Transplantation. 2013. doi: 10.3727/096368913X676222.
  160. 160. Pakzaban P, Deacon TW, Burns LH, Dinsmore J, Isacson O: A novel mode of immunoprotection of neural xenotransplants: masking of donor major histocompatibility complex class I enhances transplant survival in the central nervous system. Neuroscience. 1995;65(4):983–96.
  161. 161. Fink JS, Schumacher JM, Ellias SL, Palmer EP, Saint-Hilaire M, Shannon K, et al: Porcine xenografts in Parkinson’s disease and Huntington’s disease patients: preliminary results. Cell Transplantation. 2000;9(2):273–8.
  162. 162. Rosser AE, Barker RA, Armstrong RJ, Elneil S, Jain M, Hurelbrink CB, et al: Staging and preparation of human fetal striatal tissue for neural transplantation in Huntington’s disease. Cell Transplantation. 2003;12(7):679–86.
  163. 163. Nauert GM, Freeman TB: Low-pressure aspiration abortion for obtaining embryonic and early gestational fetal tissue for research purposes. Cell Transplantation. 1994;3(2):147–51.
  164. 164. Hurelbrink CB, Tyers P, Armstrong RJ, Dunnett SB, Barker RA, Rosser AE: Long-term hibernation of human fetal striatal tissue does not adversely affect its differentiation in vitro or graft survival: implications for clinical trials in Huntington’s disease. Cell Transplantation. 2003;12(7):687–95.
  165. 165. Petersen A, Brundin P: Effects of ciliary neurotrophic factor on excitotoxicity and calcium-ionophore A23187-induced cell death in cultured embryonic striatal neurons. Experimental Neurology. 1999;160(2):402–12.
  166. 166. Bachoud-Levi AC, Deglon N, Nguyen JP, Bloch J, Bourdet C, Winkel L, et al: Neuroprotective gene therapy for Huntington’s disease using a polymer encapsulated BHK cell line engineered to secrete human CNTF. Human Gene Therapy. 2000;11(12):1723–9.
  167. 167. Bloch J, Bachoud-Levi AC, Deglon N, Lefaucheur JP, Winkel L, Palfi S, et al: Neuroprotective gene therapy for Huntington’s disease, using polymer-encapsulated cells engineered to secrete human ciliary neurotrophic factor: results of a phase I study. Human Gene Therapy. 2004;15(10):968–75.
  168. 168. Lindvall O, Kokaia Z: Stem cells for the treatment of neurological disorders. Nature. 2006;441(7097):1094–6.

Written By

Hyun Sook Kim and Jihwan Song

Submitted: October 24th, 2014 Reviewed: April 13th, 2015 Published: December 2nd, 2015