GENE-40072; No. of pages: 7; 4C: 2 Gene xxx (2014) xxx–xxx

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Review

Huntington's disease: An update of therapeutic strategies Ashok Kumar a, Sandeep Kumar Singh b, Vijay Kumar b, Dinesh Kumar c, Sarita Agarwal a,⁎, Manoj Kumar Rana d a

Department of Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow 226014, India Department of Neurology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow 226014, India c Department of Chemistry, Dr. Ram Manohar Lohia Avadh University, Faizabad 224001, India d Department of Microbiology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow-226014, India b

a r t i c l e

i n f o

Article history: Received 9 September 2014 Received in revised form 15 October 2014 Accepted 11 November 2014 Available online xxxx Keywords: Huntington's disease (HD) htt gene Histone deacetylase inhibitors (HDACi) RNA interference (RNAi) Antisense oligonucleotide (ASO) Transglutaminase inhibitors (Tgasei)

a b s t r a c t Huntington's disease (HD) is an autosomal dominant triplet repeat genetic disease, which results in progressive neuronal degeneration in the neostriatum and neocortex, and associated functional impairments in motor, cognitive, and psychiatric domains. Although the genetic mutation caused by abnormal CAG expansion within the htt gene on chromosome 4p16.3 is identified, the mechanism by which this leads to neuronal cell death and the question of why striatal neurones are targeted both remain unknown. Patients manifest a typical phenotype of sporadic, rapid, involuntary control of limb movement, stiffness of limbs, impaired cognition and severe psychiatric disturbances. There have been a number of therapeutic advances in the treatment of HD, such as fetal neural transplantation, RNA interference (RNAi) and transglutaminase inhibitors (Tgasei). Although there is intensive research into HD and recent findings seem promising, effective therapeutic strategies may not be developed until the next few decades. © 2014 Published by Elsevier B.V.

1. Introduction Huntington's disease (HD) was first described by an American physician, George Huntington, in 1872 after he studied several affected individuals and also noted observations made by his father and grandfather (Neylan, 2003). It is an adult-onset, chronic and progressive neurodegenerative disease and clinically characterized by abnormal choreic involuntary movements and by psychiatric, psychological and intellectual disorders, and radiologically characterized by striatal atrophy of variable degree. Pathologically, in atrophied striatum, the normally predominant small projecting neurons are specifically affected. Since these neurons are inhibitory in function, their long axons terminate in the substantia nigra and use γ-aminobutyric acid (GABA) as a neurotransmitter and these GABA levels in the substantia nigra of HD are markedly low (Perry et al., 1973). On the other hand, dopaminergic nigral neurons remain intact in HD and the dopamine level in the HD striatum is higher than normal (Spokes, 1980). Therefore, HD is regarded as a relatively

Abbreviations: HD, Huntington's disease; htt gene, huntingtin gene; HDACi, histone deacetylase inhibitors; RNAi, RNA interference; ASO, antisense oligonucleotide; Tgasei, transglutaminase inhibitors. ⁎ Corresponding author at: Department of Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow 226014, India. E-mail addresses: [email protected] (A. Kumar), [email protected] (S. Kumar Singh), [email protected] (V. Kumar), [email protected] (D. Kumar), [email protected] (S. Agarwal), [email protected] (M.K. Rana).

dopamine-predominant disease. In agreement with this finding, antidopaminergic drugs are clinically effective against choreic movements. 2. Genetic insight and molecular biology of the disease HD is a single gene disease with autosomal dominant inheritance pattern and prevalence is about 5 in 100,000 worldwide (Clarke, 2005). Penetrance is almost 100% as individuals with the dominant allele eventually develop the disease. The average age of onset is 38 years, though the timing ranges from 25 to 70 years. However, approximately 5% of HD cases have presented before 20 years of age (Turnpenny and Ellard, 2007). Although the disease locus of HD was mapped to chromosome 4p16.3 by the G8 marker in the early 1980s, the HD gene was not cloned until 1993 (Gelehrter et al., 1998). HD is caused by the mutation of the gene IT15, which contains 67 exons and encodes a 3144-amino-acid protein called “huntingtin (htt)” (Young, 2005). The function of htt is unclear. It is essential for development and that absence of htt is lethal in mice (Nasir et al., 1995). HD gene is essential for post-implantation development and that it may play a significant role in the normal functioning of the basal ganglia. The wildtype htt up-regulates the expression of Brain Derived Neurotrophic Factor (BDNF) at the transcription level; however, the mechanism by which huntingtin regulates gene expression has not been determined (Zuccato et al., 2001). The normal and intermediate alleles have 10–26 and 27–35 CAG repeat respectively. Individuals with more than 39 CAG repeat will almost always show manifestations of HD (Mueller and Young, 2001), with the

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Please cite this article as: Kumar, A., et al., Huntington's disease: An update of therapeutic strategies, Gene (2014), http://dx.doi.org/10.1016/ j.gene.2014.11.022

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largest expansion observed being 121 trinucleotides (Kremer et al., 1994). CAG encodes the amino acid glutamine within the htt gene on chromosome 4, and it is not toxic in itself as it is present in all humans. However, the expansion of polyglutamine tract results in aggregate formation that may become toxic and could be one of the factors responsible for HD as aggregates are never observed in the brains of unaffected individuals (Fig. 1) (Difiglia et al., 1997; Becher et al., 1998). This aggregate formation responsible for secondary complications, like apoptosis, excitotoxicity, mitochondrial dysfunction, transcriptional dysregulation, was associated with HD and was ultimately responsible for disturbed neuropathological features (Fig. 1). Approximately 70% of the variation in the age of onset of the disease is linked to the size of the CAG repeats while 13% of the variation in the onset has been attributed to polymorphism in the GRIK2 gene, whose product forms part of the subunit of the excitatory glutamate receptor (Lutz, 2007). Therefore, there are other factors that can affect the onset, severity, and outcome of HD.

whether patients require treatment when they present. In the early stages, the chorea may not be interfering with their lifestyle and so may not require treatment. However, if the symptoms begin to affect their lifestyle such as in walking, writing and eating, then intervention becomes a necessity. The neuronal dysfunction and cell death in HD are due to a combination of interrelated pathogenic processes. Many of the compounds are being tested in cell culture and in different animal models of the disease. Currently, there are several potential therapeutic agents (memantine, tetrabenazine, minocycline, treaholose, C2–8, creatine, coenzyme Q10, ethyl-EPA, cysteamine, HDAC inhibitors, mitramicycin) mostly acting on the above-mentioned downstream targets that have shown improvement of motor and/or cognitive dysfunction mostly in the R6/2 and N171-82Q mouse lines. Up to now, seven compounds have been systematically tested in HD patients at different stages of the disease. Currently, these compounds are in phase II (creatine, coenzyme Q10) and in phase I (minocycline, cysteamine, memantine, ethyl-EPA) (Table 1). Here, we will discuss the HD therapeutics currently under development focusing on their benefits and limitations.

3. Current management and therapeutics At this time, there is no cure for HD. The majority of therapeutics currently used in HD are designed to ameliorate the primary symptomatology of the HD condition itself (psychiatric agents for the control of behavioral symptoms, motor sedatives, cognitive enhancers, and neuroprotective agents) and thus and improve the quality of life of the patients (Handley et al., 2006a, 2006b). It is important to determine

3.1. Drugs against excitotoxicity Excitotoxicity is one of the major causes of cell death in HD. Excitotoxicity relies on increased glutamate release and increased NMDAR activity, ultimately resulting in impaired calcium signaling and cell death.

Fig. 1. Proposed mechanisms of toxicity of the HD gene and potential therapeutic targets.

Please cite this article as: Kumar, A., et al., Huntington's disease: An update of therapeutic strategies, Gene (2014), http://dx.doi.org/10.1016/ j.gene.2014.11.022

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Table 1 Therapies in the pipeline targeting specific molecular mechanisms. Pipeline

Basic research

Preclinical

Phase I

Phase II

Targeting excitotoxicity Riluzole & Memantine Tetrabenazine (TBZ)

P

Targeting caspase & huntingtin (htt) proteolysis Minocycline Caspase 6 inhibitors P

P

Targeting htt aggregation & clearance Trehalose C2–8 Drugs stimulating htt clearance

Availability

P

P P P

Targeting mitochondrial dysfunctions Creatine Coenzyme Q10 Eicosapentaenoic acid (EPA) Cysteamine

P

Targeting transcriptional dysregulation Sodium phenylbutyrate HDACi 4b

P

P P P

P

Targeting mutant huntingtin RNA interference and Antisense Oligonucleotide Artificial peptides and intrabodies Targeting cell loss Fetal cells Embryonic/neural stem cells

Phase III

P P

P P

P = Present status of clinical application of specific drugs/chemicals and other therapies for Huntington disease.

3.1.1. Riluzole and memantine Riluzole (an inhibitor of glutamate neurotransmission in the CNS) was neuroprotective in chemical models of HD and in HD transgenic mice and upregulates the levels of neuroprotective factors like BDNF & Glial derived neurotrophic factor i.e. GDNF (Guyot et al., 1997; Mary et al., 1995; Palfi et al., 1997). Memantine (acts on the glutamatergic system by blocking NMDAR) may hold a more promising effect than riluzole. It reduces striatal cell death, slows down progression and leads to cognitive improvement in different HD models (Lee et al., 2006; Cankurtaran et al., 2006). However, further investigations on a larger cohort of patients will be required to confirm the neuroprotective role of the above drug in HD. 3.2. Lamotrigine, remacemide, ifenprodil, and calcium signaling blockers Lamotrigine (a glutamate antagonist) and remacemide (a noncompetitive inhibitor of the NMDA receptors) have promising results in HD mice (Ferrante et al., 2002; Schilling et al., 2001) but no significant effects on disease progression were reported (Kieburtz et al., 1996; Kremer et al., 1999). Ifenprodil [a NR2B (NMDAR subtype)-specific antagonist] reduces excitotoxic cell death in medium spiny neurons from HD transgenic and wild-type mice after exposure to NMDA (Zeron et al., 2002). InsP3R1 inhibitors (Ca signaling blockers) might be also beneficial for disease treatment (Bezprozvanny and Hayden, 2004). 3.2.1. Dopamine pathway inhibitors Dopamine is released in the striatum from nigrostriatal terminals and is neurotoxic after direct injection into the striatum (Filloux and Townsend, 1993). A hyperactive dopaminergic system could contribute to choreic symptoms and is implicated in neurotoxicity in HD (Jakel and Maragos, 2000). Tetrabenazine (TBZ), a dopamine pathway inhibitor, alleviates the motor deficits and reduces striatal cell loss and controls choric movement in HD mice, confirming that the dopamine signaling pathway plays an important role in HD pathogenesis (Tang et al., 2007; The

HDCRG, 2006). It imparts side effects such as depression, akathisia, parkinsonism and sedation but it has been recently approved by the Food and Drug Administration (FDA) for the treatment of chorea associated with HD. 3.3. Targeting caspase activities and huntingtin proteolysis The mutation of caspase cleavage sites prevents neurodegeneration and improves disease phenotype in HD mice (Graham et al., 2006). 3.3.1. Caspase inhibitors Minocycline (a second-generation tetracycline) inhibits caspasedependent (Smac/Diablo and cytochrome c) and independent (Apoptosis Inducing Factor, AIF) pathways in R6/2 mice improving the disease phenotype and neuroprotective features (Chen et al., 2000; Hersch et al., 2003). Another set of neuroprotective compounds (R1–R4 compounds) also act through a selective caspase inhibitory mechanism (caspase-3) in HD mice model (Varma et al., 2007). 3.4. Targeting aggregation The precise role of huntingtin aggregates in HD is unclear. Recent studies suggest that inclusion formation extends survival of cells expressing mutant huntingtin but further investigations are required to elucidate the pathways leading to aggregate formation, to identify the different types of aggregates that are formed during disease progression, and to discriminate which ones are protective or toxic. 3.4.1. Screens for antiaggregation compounds Congo red decreases neuronal aggregates and promotes phenotypic improvement in a mouse model of HD. It specifically inhibits polyglutamine oligomerization by disrupting preformed oligomers, prevents ATP depletion and caspase activation, preserves normal cellular protein synthesis & degradation functions and promotes the clearance of expanded polyglutamine repeats in vivo and in vitro (Sanchez et al., 2003). Similarly, disaccharide trehalose prevented nuclear inclusion

Please cite this article as: Kumar, A., et al., Huntington's disease: An update of therapeutic strategies, Gene (2014), http://dx.doi.org/10.1016/ j.gene.2014.11.022

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formation, improved motor dysfunction and prolonged survival in R6/2 mice without any deleterious side effects (Tanaka et al., 2004). Compound C2–8 improved motor performance and reduced both neuronal atrophy and the size of huntingtin aggregates (Chopra et al., 2007). Epigallocatechin-3-gallate (EGCG), the most abundant polyphenol catechin in tea, is a potent inhibitor of mutant huntingtin exon 1 protein aggregation (Ehrnhoefer et al., 2006). AGERA (agarose gel electrophoresis for resolving aggregates) is also used for resolving aggregate pools. 3.4.2. Drugs stimulating huntingtin clearance The mammalian target of rapamycin (mTOR) inhibitor rapamycin resulted in a significant reduction in mutant htt aggregates, improved neuronal survival in HD Drosophila and motor performance and striatal neuropathology in HD mice with few side effects (Ravikumar et al., 2004). However, the combined inhibition of mTOR and inositol monophosphatase (IMPase) by rapamycin and lithium respectively, resulted in additive clearance of mutant htt in vitro (Sarkar et al., 2008). While, trehalose induces autophagy of mutant htt and protect cells against subsequent pro-apoptotic insults via the mitochondrial pathway (both reduce the formation and clearance of htt aggregates) (Sarkar et al., 2007). 3.5. Drugs against mitochondrial dysfunction Mutant huntingtin binds directly to mitochondria (Choo et al., 2004; Orr et al., 2008), thereby altering their metabolic activity and motility within the cells (Orr et al., 2008). Increased mtDNA mutations and deletions that can affect mitochondrial respiration have been detected in neurons of the cerebral cortex of HD patients (Cantuti-Castelvetri et al., 2005; Horton et al., 1995). Mutant huntingtin impairs mitochondrial energy production and cellular respiration, leading to a reduction of the intracellular level of ATP, thus promoting apoptosis, oxidative stress, and susceptibility to excitotoxicity. Consequently, drugs that enhance mitochondrial function or antioxidants may represent a potential neuroprotective strategy in HD. However, to date, the majority of preclinical mouse trials designed to test the effects of different neuroprotective agents demonstrated limited success, probably because of an underestimation of the optimal therapeutic dose (Handley et al., 2006a, 2006b). 3.5.1. Creatine and coenzyme Q10 Creatine stimulates mitochondrial respiration and has antioxidant properties. It is neuroprotective in chemical and R6/2 models of HD (Ferrante et al., 2000). It reduced serum levels of 8-hydroxy-2deoxyguanosine (8-OH-2′-dG), an indicator of oxidative injury in HD (Hersch et al., 2006). Coenzyme Q10 (lipid-soluble benzoquinone) is involved in ATP production, stimulation of mitochondrial activity and neuroprotection in R6/2 and N171-82Q mice (Ferrante et al., 2002). The combination of CoQ10 and creatine produced additive neuroprotective effects on improving motor performance and extending survival in R6/2 HD mice (Lichuan et al., 2009). 3.5.2. Eicosapentaenoic acid (EPA, n−3 fatty acid) EPA causes significant improvements in multiple motor and behavioral abnormalities in different HD animal models (Raamsdonk et al., 2005). 3.5.3. Cystamine and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) blockers Cystamine and MPTP blockers inhibit oxidative damage and increase the prosurvival effects of HD cell (Mao et al., 2006). 3.5.4. Meclizine drug It silences oxidative metabolism, suppresses apoptotic cell death and acts as neuroprotective in a mouse model (Vishal et al., 2011).

3.6. Targeting gene transcription (transcription dysregulation) Transcriptional dysregulation is an early event in HD pathology and is considered to significantly contribute to the molecular pathogenesis of the disease. 3.6.1. HDAC inhibitors Transcriptional dysregulation in HD support the notion that treatment with HDAC inhibitors may ameliorate mRNA abnormalities by a direct effect on histone acetylation. Therefore, the administration of HDAC inhibitors became a good strategy to render the HD chromatin more relaxed and prone to gene transcription. SAHA (suberoylanilide hydroxamic acid) crosses the blood–brain barrier, increases histone acetylation in the brain and reduces the motor impairment in R6/2 mice (Hockly et al., 2003). Similarly, HDACi4b efficiently prevents motor deficits and neurodegenerative processes with a low toxicity profile in vitro (Thomas et al., 2008). Tubacin (selective HDAC6i) leads to rescue of the mutant htt aggregation (Iwata et al., 2005). However, Sirtuins (class III of HDAC enzymes) shows neuroprotection in HD worms (Borra et al., 2005). 3.6.2. Compounds interacting with DNA In addition to the compounds that directly interact with HDACs, compounds interacting with DNA could have a potential therapeutic value in HD, by influencing transcriptional activity. Mithramycin and chromomycin (anthracycline antibiotics) inhibit neuronal apoptosis, bind DNA and modulate epigenetic histone modifications that influence transcription (Chakrabarti et al., 2000). Furthermore, treatment with anthracycline compounds was able to rebalance epigenetic histone modification in R6/2 and N171-82Q HD mouse lines, providing the rationale for the design of clinical trials in HD patients (Ryu et al., 2006; Stack et al., 2007). 3.7. Targeting mutant huntingtin The mutant huntingtin mRNAs are targeted by the use of RNA interference (RNAi), while other strategies aim to block the protein product using small synthetic peptides or antibodies that recognize mutant huntingtin. 3.7.1. Targeting mutant huntingtin RNA: antisense oligonucleotide (ASO) and RNAi Successful delivery of ASO into NT2 cells leads to the down regulation of mutant huntingtin and reduction of aggregate formation (Nellemann et al., 2000). The ASO and RNAi perform their knock down function by nonallele-selective and allele selective manner for an e.g. modified ASO (peptide nucleic acid, PNA) enable the selective recognition of the mutant allele and the determination of the selective inhibition of mutant protein expression in human fibroblasts (Hu et al., 2009), and short hairpin RNA (shRNA) reduces mutant huntingtin mRNA and protein level in the striatum of N171-82Q mice (Harper et al., 2005). 3.7.2. Targeting the mutant protein: artificial peptides and intrabodies Intrabodies (recombinant antibodies (Abs) or Ab fragments having high specificity and high affinity to the target site) recognize the proline-rich domain of htt, improve body weight, and ameliorate motor, cognitive, and neuropathological symptoms in multiple mouse models of HD (R6/2, N171-82Q, YAC128, and BACHD) (Southwell et al., 2009). 3.8. Other therapeutics 3.8.1. Fetal neural transplantation As the striatum commonly degenerates in HD resulting in the loss of motor and cognitive functions, efforts have been made to restore these

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functions by transplanting fetal striatal neuroblasts into the striata of HD patients. However, this therapy has not been very successful in the long term. In a study by Bachoud-Lévi and colleagues in which five patients were grafted with human fetal neuroblasts, there was an increase in metabolic activity in various subnuclei of the striatum in three of the five patients, although there was a progressive deterioration in the two other patients 2 years after surgery (Bachoud-Lévi et al., 2000). However, 4 to 6 years after surgery, clinical improvement initially observed in the three patients began to decline and dystonia deteriorated consistently, while the two patients who did not benefit from the transplantation continued to deteriorate in a comparable way to non-grafted HD patients. Therefore, although neuronal transplantation may provide improvement and stability initially, it is not a permanent cure for HD (Bachoud-Lévi et al., 2006). 3.8.2. Transglutaminase inhibitor (Tgasei) Transglutaminases (as cysteamine, Q10) are a family of enzymes that catalyze the formation of a covalent bond between a free amino group and the gamma-carboxamid group of protein- or peptidebound glutamine. They form extensively cross-linked, generally insoluble protein polymers and have been implicated in a number of medical conditions such as celiac disease, Parkinson disease (PD) and HD (Griffin et al., 2002; Verme et al., 2004; Karpuj et al., 2002a, 2002b). Karpuj and colleagues demonstrated that inhibition of transglutaminase (TGase) could provide a new treatment approach to HD (Karpuj et al., 2002a, 2002b). Crosslinking is the formation of bonds to link one polymer chain to another. It is thought that this promotes the formation of the protein aggregates that cause HD. 3.8.3. Ubiquilin As expanded polyglutamine (PolyQ) tracts have been implicated in protein aggregation and cytotoxicity in HD, ubiquilin has been discovered to reduce protein aggregation and toxicity induced by PolyQ in cells and animal models of HD. Ubiquilin is an ubiquitin-like (UBL) protein and has an N terminal UBL domain and a C-terminal ubiquitinassociated (UBA) domain. Ubiquitin is a highly conserved 76 amino acid protein (Glitz, 2011) and ubiquilin-1 is one of the four members of the ubiquilin protein family. Wang and associates state that overexpression of ubiquilin decreases the aggregation and toxicity of green fluorescent protein (GFP)–huntingtin fusion protein containing 74 polyQ repeats, while a decrease in the level of ubiquilin resulted in increased aggregation and cytotoxicity (Wang et al., 2006). 3.8.4. Embroynic stem (ES) cells and germ (EG) cells ES cells are isolated and expanded from the inner cell mass of the blastocyst stage embryo. In the case of human ES cells, most currently available lines have been generated from surplus embryos following in vitro fertilization. As might be expected, these very primitive cells have the capacity to produce every cell type of the body and are capable of substantial expansion in culture, while remaining relatively stable in terms of the cell population characteristics and also having a substantial neurogenic potential (Reubinoff et al., 2000; Zhang et al., 2001). Human ES cells can be directed neurally using a variety of methods, including exposure to retinoic acid, placement of cells in serum-free medium with the mitogen FGF-2, and selection using cell-sorting methods. Studies on mouse ES cells have shown that specific neural progenitor subtypes can be derived by manipulating culture conditions to expose cells to a program of extrinsic signals that recapitulate the developmental events of neural patterning (Kim et al., 2002; Wichterle et al., 2002). EG cells, like ES cells, spontaneously form embryoid bodies (EBs), spherical structures in which cells begin to differentiate and which can form cell types from all three lineages of embryonic development. When dissociated, EB-derived cells can be vigorously and reliably expanded and efficiently cloned. The resulting cell lines predominantly express markers of the neural lineage, although markers of other lineages are also found. Their gene expression profiles appear to be

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relatively stable over multiple passages, although heterogeneous between individual lines (Shamblott et al., 1998). So far, EB-derived cells have been insufficiently characterized to properly assess their potential usefulness for neural transplantation. Although they appear to contain neural progenitors capable of robust, long-term expansion, it is not clear whether these are similar to the neural progenitors that can be derived from ES cells and whose subsequent differentiation can be controlled. 4. Conclusion and future directions The genetics and some therapeutic advances in the management of HD have been discussed. Most of these therapies focus on the development of neuroprotective strategies, with the aim of delaying the onset and slowing the progression of HD. As the onset of neurodegenerative processes begin long before the clinical manifestations of HD, it is also important to develop laboratory methods of monitoring disease progression before the onset of clinical symptoms. Most of the advances discussed are still ongoing; therefore, it is hoped that the final outcome would become more apparent in the very near future. Up to now, seven compounds have been systematically tested in HD patients at different stages of the disease. Currently, these compounds are in phase II (creatine, coenzyme Q10) and in phase I (minocycline, cysteamine, memantine, ethyl-EPA). Only one is now available in several countries (tetrabenazine). Unfortunately, only a few drugs, all belonging to oldgeneration drugs, have been tested in HD patients with some benefits. One possible explanation can be found in the discrepancies existing between mouse and human trials. These discrepancies highlight the difficulty in predicting the efficacy of new drugs in humans based on animal models of HD. All of the existing transgenic HD mouse models share features with the human pathology, but not unexpectedly, none of them individually seems to recapitulate the entire spectrum of phenotypes of human HD. Although there is intensive research into Huntington's disease and recent findings seem promising, effective therapeutic strategies may not be developed until the next few decades. This is because many of the laboratory breakthroughs prove to be unsuccessful in humans for a variety of unknown reasons. It is difficult, at this stage, to suggest that one potential treatment is better than the other as most of them have not been tried in humans so as to evaluate their effect, hence the reason why all therapeutic options should be explored by researchers. Conflicts of interest The authors have no financial conflicts of interest. Acknowledgments The authors are thankful to Sanjay Gandhi Post Graduate institute of Medical Sciences (SGPGIMS), Lucknow for providing infrastructure facility. Ashok Kumar is thankful to DBT-New Delhi (DBT-JRF 2009-10/ 515) for his fellowship. References Bachoud-Lévi, A.C., Rémy, P., Nguyen, J.P., et al., 2000. Motor and cognitive improvements in patients with Huntington's disease after neural, transplantation. Lancet 356 (9246), 1975–1979. Bachoud-Lévi, A.C., Gaura, V., Brugières, P., et al., 2006. Effect of fetal neural transplants in patients with Huntington's disease 6 years after surgery: a long-term follow-up study. Lancet Neurol. 5 (4), 303–309. Becher, M.W., Kotzuk, J.A., Sharp, A.H., et al., 1998. Intranuclear neuronal inclusions in Huntington's disease and dentatorubral and pallidoluysian atrophy: correlation between the density of inclusions and IT15 CAG triplet repeat length. Neurobiol. Dis. 4 (6), 387–397. Bezprozvanny, I., Hayden, M.R., 2004. Deranged neuronal calcium signalling and Huntington disease. Biochem. Biophys. Res. Commun. 322, 1310–1317. Borra, M.T., Smith, B.C., Denu, J.M., 2005. Mechanism of human SIRT1 activation by resveratrol. J. Biol. Chem. 280, 17187–17195.

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Please cite this article as: Kumar, A., et al., Huntington's disease: An update of therapeutic strategies, Gene (2014), http://dx.doi.org/10.1016/ j.gene.2014.11.022

A. Kumar et al. / Gene xxx (2014) xxx–xxx Young, I.D., 2005. Medical Genetics. Oxford University Press, Oxford. Zeron, M.M., Hansson, O., Chen, N., Wellington, C.L., et al., 2002. Increased sensitivity to Nmethyl-D-aspartate receptor-mediated excitotoxicity in a mouse model of Huntington's disease. Neuron 33, 849–860.

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Please cite this article as: Kumar, A., et al., Huntington's disease: An update of therapeutic strategies, Gene (2014), http://dx.doi.org/10.1016/ j.gene.2014.11.022

Huntington's disease: an update of therapeutic strategies.

Huntington's disease (HD) is an autosomal dominant triplet repeat genetic disease, which results in progressive neuronal degeneration in the neostriat...
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