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Year : 2021  |  Volume : 11  |  Issue : 2  |  Page : 95-104

Stem Cells Therapy: A Ray of Hope for Huntington Disease

1 Department of Anatomical Sciences, School of Medicine, St.George’s University, Grenda, West Indies
2 Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Mysore, India
3 Department of Biomedical Sciences, School of Medicine, Nazarbayev University, Nur-Sultan City, Kazakhstan
4 Department of Biochemistry, Panimalar Medical College Hospital and Research Institute, Varadharajapuram, Poonamallee, Chennai, India
5 Department of Biochemistry, Saveetha Dental College, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, India
6 Department of Food Science and Nutrition, and Ageing and Dementia Research Group, College of Agricultural and Marine Sciences, Sultan Qaboos University, Muscat, Oman
7 Q3CG Institute, Research & Policy Division, Ypsilanti, Michigan, USA

Date of Submission20-Oct-2020
Date of Decision19-Nov-2020
Date of Acceptance22-Nov-2020
Date of Web Publication22-Apr-2021

Correspondence Address:
PhD Saravana Babu Chidambaram
Associate Professor, Department of Pharmacology, JSS College of Pharmacy, JSS AHER, Mysuru, Karnataka 570015
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijnpnd.ijnpnd_107_20

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Huntington disease is an autosomal neurodegenerative disease that is induced by a repeated trinucleotide sequence of a gene that encodes Huntingtin and is characterized by motor, behavioral, and cognitive manifestations. It is a progressive disorder with symptoms worsening over time. The prevalence of this disease is predominant in the United States as well as the UK. The five main progression stages of this disease are Early stage, Early intermediate stage, Late intermediate stages, Early advanced stage, and Advanced stage. The risk factors at the molecular level are CAG is trinucleotide repeat, CAG instability, and genetic modification. The drugs currently used for this disease are useful only in treating the symptoms of the disease but not as useful long-term therapies. Stem cells remedy on the other hand are much more versatile and might prove effective in the treatment of neurodegeneration. Stem cells, which may be employed in Huntington research, are pluripotent stem cells, embryonic stem cells, neural stem cells, adipose stem cells, and mesenchymal stem cells. Each type of cell line has its essential properties for combating this disease. Although extensive investigations have been carried out for this disease, there is no successful therapy as of today. This review provides comprehensive information on novel stem cell therapy research that has been channeled out for the treatment of this genetic neurodegenerative disorder.

Keywords: HD, Huntington disease, neural stem cells, novel therapy, pluripotent stem cells, stem cells

How to cite this article:
Gorantla VR, Bhat A, Ghosh AR, Bolla SR, Bhojaraj S, Mohan SK, Veeraraghavan VP, Chidambaram SB, Essa MM, Qoronfleh MW. Stem Cells Therapy: A Ray of Hope for Huntington Disease. Int J Nutr Pharmacol Neurol Dis 2021;11:95-104

How to cite this URL:
Gorantla VR, Bhat A, Ghosh AR, Bolla SR, Bhojaraj S, Mohan SK, Veeraraghavan VP, Chidambaram SB, Essa MM, Qoronfleh MW. Stem Cells Therapy: A Ray of Hope for Huntington Disease. Int J Nutr Pharmacol Neurol Dis [serial online] 2021 [cited 2022 Oct 5];11:95-104. Available from:

   Introduction Top

Huntington disease (HD) is a fatal autosomal dominant neurodegenerative disorder of the central nervous system[1] clinically characterized by motor, behavioral as well as cognitive dysfunctions,[2] and its symptoms worsen over time.[3] The main cause of this disease is a repetition of a trinucleotide sequence on a gene encoding huntingtin on chromosome 4[2] and an expanded trinucleotide CAG repeat in exon 1 of the huntingtin gene (HTT). This expansion produces a toxic polyglutamine tract in the huntingtin protein (HTT).[4] HD affects men and women alike, occurring in most Western countries such as the United States with 10 out of 100 000 people being affected as well as the United Kingdom and Western European region with about 10 and 7 per 100 000 people, respectively. There are relatively lesser number of incidences in Asia and China with about 0.4 and 0.1 per 100 000 people, respectively.[5] The onset of symptoms can begin at any age, although the mean age of onset is generally between 30 and 50 years of age. The first symptoms of the disease may be physical, for example, problems with involuntary movements or coordination, and/or cognitive or psychiatric changes. Like Parkinson and Alzheimer diseases, there is no cure for this inherited disease, however, research is ongoing to find one. Identification and characterization of biomarkers have played a pivotal role in disease-modifying therapeutic approaches. Predictive (prior to symptoms) genetic testing protocols require complete knowledge of the pathogenetic mechanisms involved in HD.[2]

Stages of Huntington Disease

Stage 1: Early stage

The patient is diagnosed and remains completely functional and there are no particular signs of any impairment of motor symptoms, but there are mild cognitive and psychiatric changes. The duration of this stage is 8 years from the onset.[6]

Stage 2: Early intermediate stage

The patient can carry out regular activities but with certain difficulties and requires slight assistance and is functional at work. Irregular involuntary movements may occur and this stage may last from 3 to 13 years from disease onset.[6]

Stage 3: Late intermediate stage

The patient is no longer in a position to carry out normal household functions and requires substantial assistance for domestic duties, and thinking ability is impaired. Cognitive, psychiatric, and motor functions worsen and this stage could last for 5 to 16 years from disease onset.[6]

Stage 4: Early advanced stage

The patient may reside at home but requires assistance from family or professionals and they are not independent. The patient is aware but will require help in movement. This phase lasts from 9 to 21 years from disease onset.[6]

Stage 5: Advanced stage

These are patients at the advanced stage of HD and need total support in daily activity from professional nursing care. Speech becomes rather difficult and the patient may go through periods of confusion and screaming. Blood pressure and temperature are also affected and this stage might last from 11 to 26 years from onset.[6]

Risk Factors of Huntington Disease

Risk factors analysis identified three major molecular alterations contributing to the onset of HD:
  1. CAG repeat length in the huntingtin gene
  2. CAG instability
  3. Genetic modifiers

CAG repeat length: There have been several genetic studies on HD that have shown a correlation between the number of CAG repetition and the onset of the symptoms of the disease.[6]

CAG instability: CAG repeat mutations like other trinucleotide repeat alterations are dynamic and unstable in specific tissues as well as across generations.[6]

Genetic modifiers: Genetic modifiers are genetic factors that have been identified by means of candidate gene approach and have a lesser overall effect. They were found to be different from CAG mutation in the Huntington gene. Genetic factors are believed to be one of the main risks contributing to the onset and outcome of the disease. In future research, these genetic modifiers may assist in the identification of therapeutic targets for HD.[7]

Pathophysiology of Huntington Disease

[Figure 1] depicts an overview of the pathophysiology of Huntington’s disease involving the GABAergic system. The Huntington gene is located at chromosome 4p16.3 and encodes for the Huntingtin protein (family of expanded CAG repeat disorders, with spinal and bulbar muscular atrophy). It is highly expressed in neurons and has a size of 348 kDa. It is primarily cytoplasmic but also localized at the nucleus as well as organelles.[8] The CAG expansion, as well as the polyproline region of the N-terminus are responsible for the pathophysiology of the disease. Mutant strains of Huntingtin undergo N-terminal cleavage forming polyglutamine fragments, which is eventually followed by oligomerization and cytoplasmic and nuclear localization. The N-terminal fragments, oligomers of these fragments, and the fully formed inclusions have been implicated in the toxicity of HD.[8] This leads to the disruption of several cellular processes[8],[9] such as:
  1. Mitochondrial dysfunction
  2. Transcriptional dysregulation
  3. Altered axonal transport of critical factors
  4. Disrupted calcium signaling
  5. Abnormal protein interactions
  6. Impaired autophagy
Figure 1 HD pathophysiology. An overview of the pathophysiology of Huntington’s disease involving the GABAergic projections.

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Current symptomatic treatment options for Huntington disease

Although there has not been any successful cure for this disease, significant research has been carried out to provide symptomatic relief to patients. The following categories of drugs described below are useful in such instances. [Table 1] provides examples of drug name, drug chemical structure, and the symptomatic treatment options for Huntington’s disease.
Table 1 Symptomatic treatment options for Huntington disease.

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Dopamine antagonists

Two theories are reported on the mechanism of action. The first one involves blocking of postsynaptic dopamine D2 receptors (suppresses chorea).[10] The second theory suggests that symptomatic relief is due to its sedating effects.[11] Tiapride, Clozapine, and Olanzapine present option treatment in this case.


One type of chemical messenger known to be affected in Huntington’s disease is gamma-aminobutyric acid (GABA). Because individuals with this disease have reduced levels of GABA in the brain thus resulting in anxiety, this category of drugs works by enhancing GABA action making the neurons become lesser active and therefore combating anxiety.[12] Lorazepam and Alprazolam are examples of intermediate-acting benzodiazepines whereas Clonazepam and Diazepam are examples of long-acting benzodiazepines that are practiced in treating anxiety in HD.

Glutamate antagonists

These drugs have been proven useful in clinical trials.[13] Although proven successful against chorea and improvement in motor scores, the majority of these drugs have shown adverse effects. Among the drugs, Amantadine has proven useful against choreicdyskinesias in some patients. Others include Remacemide, Riluzole, and Ketamine.[13],[14]

Acetylcholinesterase inhibitors

Acetylcholine is essential for the cognitive function of the brain and one of the symptoms of the onset of HD is cognitive dysfunction.[15] It includes psychomotor symptoms, visuospatial deficits, perceptual deficits, memory loss as well as trouble in learning new skills.[16] The brain undergoes certain structural and functional deficits,[17] which eventually leads to frontal and subcortical dementia.[18] Decreased acetylcholine levels have been noted in HD patients.[19],[20] Hence, acetylcholinesterase may be useful in increasing the acetylcholine levels and thereby improving the loss of cognitive impairment. Examples in this category are Galantamine and Rivastigmine.


Cannabinoid receptors (CB1) are modulators of neurotransmitters in the brain and are present in abundance in basal ganglia.[21],[22] These CB1 receptors play a major role in the motor responses.[23] Activation of these receptors decreases locomotion, whereas antagonizing of these receptors results in hyperlocomotion.[24],[25] Endocannabinoids reduce the effects of neurodegeneration and were shown to protect neurons via CB1 receptor-mediated inhibition of glutamate exocytosis as well as closing voltage-sensitive calcium channels and reducing anti-oxidant activity[26],[27] like Nabilone and Synthetic Δ9-tetrahydrocannabinol.


Lithium has long been shown to have a wide range of molecular effects. It is involved in several pathophysiological changes such as oxidative stress, apoptosis, inflammation, environmental stress, glial dysfunction, neurotrophic factor deficiency, excitotoxicity as well as mitochondrial and endoplasmic reticulum disruption.[41] Lithium acts by inhibiting a protein kinase called glycogen synthase kinase 3 (GSK-3), a serine/threonine-protein kinase that functions in intracellular signal transmission by protein phosphorylation. Inhibition of this enzyme appears to have a neuroprotective effect in neurodegenerative diseases such as HD.[42]

Deep brain stimulation

Research suggests that this involves multiple mechanisms, including shaping the electrical and neurochemical activity of brain cells near the electrode. It also modulates neural network activity in the brain in general.[43]

Cell-based Treatments for Huntington Disease

Gene therapy

Ideal gene therapy for HD is to target and reduce the transcript of an mHTT allele with RNAi or antisense oligonucleotides (ASOs) without affecting the normal functioning of HTT.[44],[45],[46] Recent studies have shown that it is possible to decrease the mHTT levels that directly correlates to the knockdown of mutant and normal alleles of HTT transcript in RNAi mouse models.[47] Davidson group reported that short-hairpin RNA (shRNA) is more potent and displays better safety profiles than miRNA in knocking down mHTT in rodent models. However, a drawback it results in higher levels of cell toxicity compared to miRNA.[47] RNAi approaches that non-specifically target both mutant and normal alleles have raised serious safety concerns. The normal physiological role of HTT remains largely unknown, moreover, HTT knockout mice are embryonically lethal.

Cell-based Therapy for Huntington Disease

Stem cell therapy

Stem cells have major advantages in transplantations as they are undifferentiated and omnipotent in nature and consequently they are capable of differentiating and giving rise to several types of cells with lesser chances of any kind of immune rejection.[48],[49] They also possess self-renewal properties and can differentiate into a variety of cell types [Figure 2].
Figure 2 Differentiation process of stem cells. When the sperm and oocyst combine to form the fertilized egg, it results in the multiplication of the cells mitotically to produce a cluster of cells (Morula). This step is followed by the formation of a cavity in a cellular mass known as Blastocyst. This initially leads to the formation of pluripotent stem cells and eventually results in differentiation and formation of pluripotent stem cells. This pluripotent stem cell further differentiates into Neural stem cells and the formation of neurons, astrocytes, and oligodendrocyte takes place by means of factors such as FGF and SHH. The formation of hematopoietic stem cells is followed by differentiation into WBC and RBC cells by means of factors such as EGF, FGF, and GDF. Mesenchymal stem cells are differentiated further into bone and cartilages by means of growth. SHH, Sonic hedgehog factor; EGF, epidermal growth factor; FGF, fibroblast growth factor; GDF, growth differentiation factor.

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The various types of stem cells that have been employed in HD’s research are:
  1. Neuronal stem cells (NSCs)
  2. Mesenchymal stem cells (MSCs)
  3. Adipose-derived stem cells (ASCs)
  4. Induced Pluripotent stem cells (iPS cells)

These are generally isolated from specific adult human tissues. However, Takahashi and Yamanaka group recently induced pluripotent/ESC-like cells from somatic cells, and these are named induced pluripotent stem cells (iPS cells).[49]

Induced pluripotent stem cells for Huntington disease

The (HD iPSC Consortium, 2012) worked on a study that involved a set of CAG repeat expansion phenotypes in neural cells that had been derived from HD iPSC lines. These involve a number of cellular assays. In this particular disease, a close relationship was identified between the gene and the expanded CAG repeat length. There was a strong correlation between the length of the expanded repeat and the rate of progression of motor and cognitive disorder.[49] The studies carried out on HD60 and HD180 cell lines were tested for cellular aggregation, energy metabolism, and cumulative risk of death overtime (long differentiation protocol). Both of these cell lines exhibited similar pathological profiles that were different from control cell lines. The robust phenotype of HD180 cell line was revealed by cell survival (short differentiation protocol), brain-derived neurotrophic factor, and Glutamate toxicity. Calcium homeostasis followed by glutamate pulsing, graded responses on the cell lines HD33, HD60, and HD180 indicated a repeat dependent phenotype. The gene array study conducted proved that there was a clear difference between the gradation of expression changes in very long repeats (HD180 and HD109) and moderate length repeats (HD60).[49] These studies suggest that there is a correlation between the phenotypes and expanded CAG repeats. The choice of the assay and the tissue determines the extent of the phenotypic gradation that depends on the length of CAG expansion.[49] The aim of these studies was to determine the neuronal properties of HD-iPSC derived from an HD patient carrying a maximum of 72 CAG repeats. Even though the initial differentiation was lower than human embryonic cell culture, it was demonstrated that HD-iPSC could successfully produce GABAergic projection neurons that resemble medium spiny projection neurons (most commonly seen in HD patients).[37} These neurons survive even after transplantation into the striatum of the rat model of HD and hence show significant behavioral recovery. It was realized that there is no appearance of huntingtin aggregation during the in vitro culture but after treatment with a proteasome inhibitor (MG132) and long-term exposure of about 33 weeks huntingtin aggregation is clearly visible. This shows that the HD-iPSC that carries the 72 CAG repeat sequence is susceptible to proteasome inhibition in the later stages, although it forms GABAergic neurons and considerable recovery at early stages in in vivo models is evident. Hence, it may be used as an experimental platform to study the HTT disease pathology and develop several new drug screening methods.[50]

Significant research has been conducted on stem cells and it is apparent that stem cell therapies are promising in the treatment of neurodegenerative diseases, especially pluripotent stem cells. The use of these stem cells has been studied due to their potential to generate neuronal cells and their effective use in animal models. Toward this end, neural progenitor cells (NPCs) have two main advantages. They can be engrafted into the brain in animal models and can differentiate into neuronal cells additionally they can promote behavioral and motor recovery. Although there has been significant progress using PSC, there is a need to overcome tumorigenicity. Nevertheless, these HD-PSC cell lines can be useful as models for basic research in vitro.[51]

Szlachcic et al.[52] using iPSC models showed that there is a significant alteration in molecular pathways by the mHTT (mutant).[52] Hence, the effects of gene silencing were tested on HD iPSC cells of HTT. Several shRNAs targeting this protein in the model of YAC128 iPSC, human HD109, HD71 were investigated in these cells. The shRNAs were successful in silencing all of the iPSC cells and remained active till the differentiation to neural stem cells. It was later found that the levels of mHTT were inversely proportional to the levels of p53. It was observed that the reduction in the levels of mHTT resulted in the normalization of the levels of p53. Other investigations on gene silencing were the silencing of the proteins of Wnt/β-catenin and ERK1/2 signaling pathways. The two major studies performed in this area are as follows:
  1. The production of human shRNA-expressing HD iPS cells with stable and continuous HTT silencing
  2. Reversal of p53 phenotype in mouse HD models

Recent studies using the genome editing technologies and the introduction of revolutionary technologies for gene editing have now made it possible to study human diseases even at cellular and molecular levels. The gene-editing tools that may be useful are the following:

Zinc finger nuclease (ZFN), Transcription like activator effectors (TALEN), (Clustered Regulatory Interspaced Short Palindromic Repeats)/Cas9 (CRISPR/Cas9) based systems, NgAgo, and structure-guided nuclease (SGN).

Bailus et al.[53] utilized TALENs and CRISPR technology to model HD-relevant cell types and better understand disease progression in isogenic iPSC lines and identified transforming growth factor β (TGF-β) signaling, netrin-1 signaling, and medium spiny neuron (MSNs) maturation and maintenance are the most dysregulated pathways in HD NSCs. Using cells from people with HD and in mouse models of the condition, Davidson’s team demonstrated last year that CRISPR achieves the same benefits through a single dose because it permanently inactivates the defective gene with remarkable efficiency.

These tools are useful in inducing modifications in gene sequences and regulation of gene expression in several types of cells especially pluripotent stem cells (iPSC).[54] These tools may be useful for HD modeling process by generating isogenic cell lines that possess different numbers of CAG repeats or in cases of correction of mutations. Although very few researchers are working on HD using gene-editing tools, it may be very useful in studying the pathways of HD and confirming any of the current hypotheses for this disease.[54]

Camnasio et al.[55] established that in vitro models may replicate the conditions of the disease and help in understanding the cellular and the molecular events that result in the manifestation of the symptoms of this disease. In this study, two types of induced pluripotent stem cells were studied from the HD patients, namely, two rare homozygous genotypes and one heterozygous genotype. Pluripotency and differentiation were confirmed by means of polymerase chain reaction amplification and immunocytochemistry where the expression of the marker genes was observed. Teratomas are formed in the iPS cells. It was observed that there was no increase in lysosomal activity in HD-iPS cells and the length of CAG repeat did not increase on reprogramming. It was established that HD-iPS cells can be ideal to study the mechanisms of HD.[55]

Mesenchymal stem cells for the treatment of Huntington disease

Olson et al.[56] investigated the use of mesenchymal stem cells in the treatment of neurodegenerative diseases mainly Huntington’s disease This treatment approach is currently in phase I to III clinical trials. In preclinical studies, these cells have shown an increased efficacy when used as a delivery vehicle for neural growth factor. This treatment option of using MSC-secreted trophic factor balances the impaired functions of the injured neurons (overexpression of brain-derived neurotrophic factor and glial-derived neurotrophic factor). This method involves the MSC to directly deliver the cytokines to this microenvironment.[56]

The hypothesized regenerative approaches using MSC include cell therapies using intracerebral and intrathecal injections. These therapies cause the following:
  1. Promotion of endogenous neuronal growth
  2. Increase in the synaptic connection from damaged neurons
  3. A considerable decrease in apoptosis
  4. Reduction of the levels of free radicals
  5. Regulation of inflammation

Researchers have worked on RNA interference (RNAi) technology and have demonstrated a lot of successful results in transgenic mouse models of HD by suppressing the mutant transcript of HTT. Although these investigations have shown successful results in model organisms, clinical trials of these studies have not been very successful. This is due to the inability to deliver RNAi to the affected neurons in a concise manner.[56]

On the contrary, MSC have shown a strong safety profile in ongoing research. They exhibit therapeutic effects in damaged microenvironments of immune modulation, and homing to injury and cytokine release.[56] MSC have shown the ability to successfully transfer larger molecules and have been shown to be useful as delivery agents for RNA inhibition.[56] There were a series of model systems that have provided sufficient evidence that these MSC can target reporter genes (which enable detection and measurement of gene expression) using RNAi. InSH-SY5Y cell line, MSC expressing antisense shRNA was found to decrease the expression of green fluorescence protein (GFP) when assayed by flow cytometry.[56] Additionally, assays performed by western blotting and densitometry reported that modulation of the levels of mHTT in target cells of U87 and SH-SY5Y may be useful in expanding the potential of RNAi and MSC in the future to combat HD.[56]

Moraes et al.[57] demonstrated that labeling of superparamagnetic iron oxide nanoparticles (SPION) with MSC is safe and feasible. Because this disorder involves the deletion of striatal GABAergic neurons, this study involved injecting the MSC labeled with SPION into the striatum after an hour of quinolic acid injection.[57] It was identified that this transplantation aided in the decrease in the large CSF-filled structures in the brain known as ventriculomegaly in presence of these cells that were detected by MRI and histological techniques for 60 days. According to these data, it is obvious that these MSCs are an essential tool in reducing any sort of brain and neuronal damage.

Induced neural stem cells for treatment of Huntington disease

Biochemical pathway and molecular mechanism analyses in HD have identified potential therapeutic targets. Potential targets may be involved in the alteration of cellular stress to pathogenic aggregates, dysregulation of transcription, protein interactions of abnormal might, identifying epigenetic modifiers such as HDAC inhibitors.[58] However, a great deal of work is required to understand and provide treatment options for any kind of cellular dysfunction and avoid MSN destruction. HD-iPSC models are a promising area as they can be directly reprogrammed from patients’ somatic cells as well as serve as a cellular disease model. Mechanism and neurogenesis may be studied using cell engineering technologies. However, investigations on their efficacy have not yet been demonstrated. The direct lineage reprogramming technology may convert somatic cells to induced neural stem cells (iNSC) that could differentiate into functional GABA MSNs. These can then be transplanted into the brain for recovery of motor as well as cognitive function.[58] Further studies are required to establish the in vitro differentiation of functional MSNs that may prove as reliable markers as well as determine the safety and efficacy of pluripotent or iNSCs for clinical applications.[58]

Embryonic stem cells for the treatment of Huntington disease

A study was done to understand the pathophysiology of HD that revealed the major cause to be the degeneration of medium spiny GABA neurons present in the basal ganglia for which at present any kind of effective therapy is not available. Human embryonic stem cells were enriched with Dopamine and cAMP-regulated phosphoprotein of 32 kDa (DARPP32)- expression in the forebrain GABA neurons.[59] Henceforth, transplantation of these human forebrain GABA neurons into striatum quinolinic acid-lesioned mice results in the generation of large populations of DARPP32+GABA neurons project into the substantianigra receiving glutaminergic and dopaminergic inputs to modify and correct any form of motor deficits. This finding raises hopes for cell therapy in HD.[59]

   Conclusion Top

HD is a progressive neurodegenerative disease and therapies so far have only been useful in treating the symptoms effectively. However, as there is no successful therapy for this disease, progression of the disease and death of the individual is inevitable. The current therapies do not treat the motor, behavioral, and cognitive features effectively, but there has been some significant advancement in the areas of research on new therapies and several have reached clinical trials. There is still some hope for clinical advancement and an effective cure will change the outcome of this disease in the future. Stem cells offer that ray of hope.


The authors want to thank their respective institutions for their continued support.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

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This article has been cited by
1 Non-Cell Autonomous and Epigenetic Mechanisms of Huntington’s Disease
Chaebin Kim, Ali Yousefian-Jazi, Seung-Hye Choi, Inyoung Chang, Junghee Lee, Hoon Ryu
International Journal of Molecular Sciences. 2021; 22(22): 12499
[Pubmed] | [DOI]


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