Multimodal treatment strategies in Huntington’s disease

Huntington’s disease (HD) is an incurable neurodegenerative disease that causes involuntary movements, emotional lability, and cognitive dysfunction. HD symptoms usually develop between ages 30 and 50, but can appear as early as 2 or as late as 80 years. Currently no neuroprotective and neurorestorative interventions are available. Early multimodal intervention in HD is only possible if the genetic diagnosis is made early. Early intervention in HD is only possible if genetic diagnosis is made at the disease onset or when mild symptoms manifest. Growing evidence and understanding of HD pathomechanism has led researchers to new therapeutic targets. Here, in this article we will talk about the multimodal treatment strategies and recent advances made in this field which can be used to target the HD pathogenesis at its most proximal level.

HD is an inherited degenerative condition of brain cells, characterized by gradual development of involuntary movement of muscles, deterioration of cognitive processes leading to dementia, and psychiatric and psychosocial disturbances. It is caused by an expanded CAG glutamine codon repeat in exon 1 of huntingtin (HTT) gene, which encodes huntingtin [1-4]. Linkage analysis mapped the genetic defect to chromosome 4p16.3 using linkage analysis [5]. The average age of onset is 40 years followed by an unrelenting progression and average survival of 15–20 years [6].

Putative polymorphic HTT repeat is commonly seen in the normal population [7], but people who inherit >35 CAGs are prone to have HD. Rubinsztein, et al. reported >40 CAG repeats are fully penetrant within a normal lifespan [8]. Very frequently, germline instability is seen in expanded repeats in HD patients which may not have a CAG repeat length similar to their transmitting parent [9-11]. Intergenerational expansion of a normal length CAG repeat may be the reason behind sporadically generated rare de novo cases of HD in general population [12,13].

Longer repeat lengths have been shown to lead to earlier onset disease of increased severity [14]. However, genetic modification of additional loci can influence onset and progression of the disease [15]. Meta-analyses show a worldwide prevalence of 2.7 per 100,000 with the highest rates in Western populations and lowest among Asians [16,17]. Symptomatic treatment of chorea remains the only approved indication in HD with drugs such as vesicular monoamine 2 transporter (VMAT-2) inhibitors or neuroleptics [18].

The role of HTT is considered as a scaffold that engages with many other proteins and cellular mechanisms [19]. Mutant HTT (mHTT) contains an expanded polyglutamine tract near the amino terminus. This leads to misfolding that triggers a cascade of pathogenic processes. These are driven by mHTT being unable to perform normal functions and the accumulation of toxic species from various permutations of aberrant mRNA splicing, translation and subsequent mHTT proteolytic cleavage [20,21], and accumulation of toxic aggregates. However, a definitive correlation is yet to be established, as HD mouse model studies have demonstrated neuronal loss in the absence of aggregates [22] and aggregates in the absence of neuronal dysfunction [23].

Striatal medium spiny neurons (MSNs) are selectively vulnerable to mHTT through multiple mechanisms, including but not limited to, the loss of trophic support (in particular, the reduction in brain-derived neurotrophic factor - BDNF), immune dysregulation, synaptic dysfunction (excitotoxicity), altered cellular homeostasis and impaired mitochondrial function [6]. mHTT accumulates in glial cells leading to reactive astrocytosis and microgliosis that can accelerate atrophy [24]. Coup-TF interacting protein 2 (CTIP2), a transcription factor that is expressed abundantly by all MSNs is known to interact with mutant huntingtin and is implicated in human MSN homeostasis and striatal neurodegeneration [25].

Therapeutic approaches

HTT lowering: Lowering HTT levels has become one of the most intriguing and promising emerging therapeutic options with disease modifying potential.

RNA based approaches: HTT pre-mRNA can be targeted using antisense oligonucleotides (ASOs) and mature ribonucleic acid (mRNA) with interfering RNA (RNAi), both of which enhance early degradation and lower levels of mHTT [26]. ASOs are single-stranded deoxyribonucleotide capable of altering mRNA expression through several mechanisms, including direct steric blockage, inhibition of 5′cap formation, ribonuclease H mediated decay of the pre-mRNA, and exon content modulation through splicing site binding on pre-mRNA. The goal of the antisense approach is to influence certain protein production. Once inside the cell, the ASO binds to the target mRNA or pre-mRNA, inducing its degradation and preventing the mRNA from being translated into a detrimental protein product [26,27].

Blood-brain barrier (BBB) is impermeable to ASOs, therefore it has to be administered directly to CNS. An animal study showed when ASOs were tagged with arginine-rich CPPs and systemically delivered, resulted in BBB crossing and got widely distributed in brain [28]. ASOs can be allele specific or non-specific. Development of RNAi-based strategies to silence or edit HTT are currently in preclinical phases. Potential modalities include employing small-interfering RNA (siRNA) or short-hairpin RNA (shRNA) [29], artificial microRNA (miRNA) [30]. Double-stranded RNA (vs. single-stranded ASOs) has low diffusion and CNS uptake thereby requiring this strategy to utilize a viral vector, such as an adeno-associated virus (AAV) containing complementary DNA, to introduce the RNAi [26,31]. The RNAi will then bind mature mRNA from the mutated gene. There have been promising preclinical results in HD models [32,33].

AAV vectors have become popular in studies of neurodegenerative disease due to their low immunogenicity, non-pathogenicity and efficient transduction of brain cells [34]. Serotype AAV9 crosses the BBB easily and is being increasingly used in treatment of neurological conditions. Presumably, this modality will allow for sustained and long-term target silencing after a single administration [35]. Less invasive, systemically administered RNAi has shown promise in HD mouse models [36] but not primates [37].

Isabel Pérez-Otaño, et al. in their study showed motor impairment and corticostriatal dysconnectivity in HD can be reversed by silencing GluN3A, which is glycine binding subunit belonging to the N-Methyl-D-aspartate (NMDA) receptor family, and thereby supported the use of RNAi-based approach for utilization of this therapeutic model [38]. Matthes, et al. in their HD cell line mode study showed furamidine decreases protein level of HTT [39].

Recently, Ramos, et al. suggested intranasal administration of nanoparticles carrying siRNA as a promising therapeutic alternative for safe and effective lowering of mutant HTT expression [40]. Previously, Miniarikova, et al. has reported suppression of mutant huntingtin aggregation in neurons and neural dysfunction in a rat model of HD by using AAV5-miHTT gene therapy [41].

This gene therapy lowered HTT but no immune response was initiated due to non-activation of astrocytes or microglia. These findings may interest researchers in using gene therapy in knocking down HTT which may benefit HD individuals clinically and symptomatically [42].

Tominersen, previously known as IONIS-HTTRx and RG6042 is allele non-specific. It forms a hybridized complex that is degraded through an RNAse-H1 mechanism. A very significant reductions of disease-causing mutant huntingtin protein in people with HD was seen [43,44].

Datson, et al. in their study reported changes in brain anatomy and chemical milieu which led to the improvement of motor performance, suggesting that treatment with (CUG)7 may ameliorate basal ganglia dysfunction in HD patients. A study done in Q175 mice using an identical (CUG)7 AON dosing regimen confirmed lowering of HTT. An increase in motor activity with significant decrease in mHTT in cortex, hippocampus, and striatum lasting up to 18 weeks post last infusion was observed. The authors believe (CUG)7 can be used in lowering HTT in HD individuals [45].

Keeler, et al. in their study reported lowering of mRNA expression of HTT in striatum by 50% when intrastriatal infusion of an AV9-GFP-miRHTT vector was given. The main reason behind this finding was partial reduction in the number of copies of mHTT mRNAs per cell [46].

Recently, a report suggested a distinct delay in the differentiation of the juvenile onset HD (JHD) neural progenitor population. However, the authors think this reduction of the JHD aberrant progenitor populations can be accomplished by treating either with HTT ASOs or targeting the notch signaling pathway [47]. Therefore, in principle, a single stereotactic intrastriatal injection may be all that is needed, which although still invasive, may provide some advantage over the repeated injections in ASO-based strategies. On contrary, potential advantage of ASOs over RNAi-based modalities is that ASOs can be taken up by multiple CNS cell types with high efficiency without the need for a carrier [48].

DNA based approaches: Most common approaches are through naturally occurring proteins, ZNFs and genome editing tool CRISPR/Cas9 which has gained much attention recently. ZFPs are a diverse group of naturally occurring proteins that are able to interact with deoxyribonucleic acid (DNA) and modulate transcription [49]. They are engineered to bind to any DNA sequence, with preference for longer CAG repeats in the case of HD mouse models and human cells [50,51]. After delivery with an AAV, they can bind to transcriptional repressor domains and was shown to selectively suppress mHTT expression [50]. A study has reported in HD mouse models, ZFPs were able to reduce mHTT levels and an HD-like behavioral phenotype [51].

CRISPR/Cas9 edits genes by precisely cutting DNA and then letting natural DNA repair processes to take over [52,53,54]. Recent, evidence showed complete suppression of mHTT in the striatum of HD mouse models with attenuation of neuropathological changes [55]. Shin j, et al. demonstrated inactivation of the mutant allele using haplotype-specific CRISPR/Cas9 target sites in HD. They were able to completely prevent the generation of mutant mRNA and mHTT in patient-derived fibroblasts [56]. Pan, et al. observed any disturbances in DNA methylation play a critical role in mHTT induced neuronal dysfunction and death in HD. Additional preclinical studies are required to validate CRISPR-based strategies in HD before they can be developed into clinical trials [57].

HTT modulation

Selisistat: Sirtuin activity modulation enhance clearance of mHTT. Sirtuins are NAD dependent deacetylases involved in metabolic regulation and neuroprotection through either overexpression or inhibition of various sirtuins [58-60]. Post-translational modification of proteins such as acetylation of mHTT promotes its clearance, clearly linking it to autophagy by the autophagic-lysosomal pathway [61].

SirT1 (silent information regulator T1) is a member of the sirtuin family. It is a NAD dependent deacetylase and removes acetyl groups from lysine residues in many histone and nonhistone proteins and other proteins including mHTT [61-63]. A study reported that inhibition of SirT1 in transgenic Drosophila and R6/2 mice resulted in selective decrease in mutant HTT protein levels [63]. These abovementioned studies made researchers around the world to hypothesize that inhibition of SirT1 results in the selective clearance of mHTT without affecting normal protein levels.

Selisistat is a selective SirT1 inhibitor that inhibits recombinant human SirT1 both in vivo and vitro [64]. It exhibits neuro and cytoprotective activity against toxicity induced by mHTT in cellular and in vivo models of HD. It has been linked to increased survival rate and improvement of behavioral impairment [65].

A larger study of 125 patients randomized to 50 or 200 mg selisistat over 12 weeks also demonstrated safety and tolerability except for reversible increases in liver function tests [66]. No significant differences between selisistat and placebo groups has been observed and currently no phase III trials are ongoing, and further development appears to be on hold.

Hydroxyquinoline (PBT2): It is considered as a metal chaperone [67]. PBT2 is a moderate-affinity 8-hydroxyquinoline transition metal-ligand that acts as a synthetic chaperone, redistributing copper, zinc, and iron from locations where they are abundant to subcellular locations where they might be deficient. Delivery of copper and zinc by PBT-2 into the cytoplasm deactivates the kinase glycogen synthase kinase 3β and the phosphatase calcineurin both potential targets for HD.

PBT2 is able to protect against glutamate-induced neural excitotoxicity mediated through NMDARs. This phenomenon is attributed to PBT2 inducing Zn2+-dependent increases in intracellular Ca2+ levels resulting in preconditioning of neurons and inhibition of Ca2+-induced neurotoxic signaling cascade involving calpain-activated cleavage of calcineurin. [68]. PBT2 was considered safe and well tolerated, however, the FDA issued a Partial Clinical Hold in 2015 (in effect) due to safety concerns of the 250 mg dose and require more data for this to be lifted [69,70].

Immunomodulation

Plasma levels of a specific cytokine, interleukin 6 (IL-6) have been shown to correlate with disease progression in premanifest HD individuals. Increased microglial activation in the brain also leads to abnormal proinflammatory profiles that correlate with progression and can predict disease onset. Several proinflammatory cytokines are present in the CSF of HD patients in addition to abnormal blood chemokine profiles [71]. These chronic state of neuroinflammation likely stems from a reactive response to mHTT-induced neurodegeneration as well as the cellular dysfunction associated with mHTT expression itself [72].

Laquinimod: Laquinimod is an immunomodulatory agent under clinical development for HD. In the YAC128 HD mouse model, behavioral improvements along with prevention of shrinking of the white matter rich corpus callosum was seen. Laquinimod was able to preserve myelin in the posterior region of corpus callosum, thereby increasing myelin sheath thickness and rescuing myelin basic protein mRNA and other important protein deficits.

Furthermore, the levels of the Mbp and Plp1 transcripts were also increased in the striatum which shows that role of laquinimod on myelin-related gene expression was not region-specific. The authors believe HD-related demyelination in YAC128 HD mice did not depend on the immunomodulatory effect of laquinimod [73].

Laquinimod might influence BDNF-dependent pathways in HD. However, mild changes are seen in striatal histopathology and motor functionality [74]. A recent study on YAC128 model of HD reported modest behavioral improvements and preservation of cortical, striatal, and white matter [75].

Post DNA damage, Laquinimod reduces the basal expression of Bax in primary neurons and reduces neuronal caspase-6 activation. Laquinimod have direct effect on astrocytes and microglia and can halt axonal degeneration by downregulating neuronal apoptosis and may provide some clinical benefit [76].

Semaphorin 4AD: Semaphorin 4AD (SEMA4D) is also known as Cluster of Differentiation 100 (CD100). It is a protein of semaphorin family and is encoded by the SEMA4D gene. It is an axon guidance molecule which is secreted by oligodendrocytes and induces growth cone collapse in the central nervous system [122]. It is responsible for chronic inflammation in brain, halts neural development, apoptosis, breakdown of BBB, and neurodegeneration.

VX15/2503 is an antibody developed by Vaccinex, which prevents brain inflammation by blocking the activity of SEMA4D. This antibody is responsible for maturation of specific cells which is turn repairs myelin loss. Several preclinical studies in animal models have showed the efficacy of this antibody against brain atrophy. It is also known to prevent spatial memory loss and suppress anxiety.

A 12-month intravenous treatment with VX15/2503 was safe and a follow-up of three months did not show any undesired side effects and was well tolerated. Patients treated with this antibody stabilized Huntington’s related brain atrophy and showed improvement in metabolic activity over placebo [77-79].

Synaptic modulation

Synaptic dysfunction is a well-defined mechanism of HD pathogenesis. Excitotoxicity through synaptic connections with striatal MSNs may be mediated through various neurotransmitter receptor pathways thereby offering themselves as potential therapeutic targets [80].

Pridopidine: It has much higher affinity for the sigma-1 receptor (SIG1R) [81], and various other mechanism of action [82]. This chaperone function has been shown to be abnormal in HD models [83]. Subsequently, when a SIG1R agonist (PRE084) was used in neuronal cells expressing mHTT, it demonstrated improved survival [84]. Raymond, et al. reported on the disruption in homeostatic synaptic plasticity, known to enable new learning and cognitive flexibility. This disruption was restored by stimulation of SIG1R, which should be studied for developing treatment strategy to alleviate cognitive impairment in HD [85].

The neuroprotection exerted by pridopidine in HD cell models is SIG1R dependent. Pridopidine and S1R agonists can act as neuroprotective agents in HD which should be studied in large trials [86].

Pridopidine was shown to restore transcriptomic disturbances in the striatum, increase transcription across synapses, and activating neuroprotective pathways affected in HD [87]. Marta, et al. showed pridopidine if taken in early stages in HD exerts beneficial effects at the transcriptional level and improvement in behaviour [88].

Unfortunately, pridopidine did not significantly change the UHDRS-TMS at 26 weeks compared to placebo at any dose in PRIDE-HD trial. Serious adverse events like aspiration pneumonia, head injury, falls etc. occurred in the pridopidine group only. A phase III study has been considered. Teva Pharmaceuticals has announced a halt to further development at this time however its future is uncertain at this moment [89].

Phosphodiesterase 10A inhibitors: PDE10A inhibitors are known to have antipsychotic property and are also thought to be neuroprotective [90]. PDE10A is abundant in striatum and is a key regulator of basal ganglia circuitry modulating cortical motor activity. Diggle, et al. reported two families comprising of eight individuals with germline PDE10A mutations affected with hyperkinetic movements due to homozygous mutations [91].

TAK-063, a novel PDE10A inhibitor, halts neurodegeneration in striatum and improves behavioral deficits in the R6/2 mouse model of HD. It ameliorated deficits in procedural learning, but was ineffective for deficits in contextual memory [92].

Early chronic PDE10 inhibition rather than acute administration after onset of symptoms in Q175 mice showed drastic response in the form of partial reversal of striatal deregulated transcripts and prevention of occurrence of neurophysiological deficits [93].

Memantine: Coordinated structural and functional connectivity is disrupted by hyper-excitability in HD. Memantine as a NMDA antagonist can reduce the excitotoxicity and normalize the brain connectivity [94]. Chidambaram, et al. reported simultaneous blockade of NMDAR and suppression of PARP activity is necessary to ameliorate immune-excitotoxicity and improve bioenergetics in 3-NP induced neurodegeneration. Treatment with MN+3-AB can be an efficient regimen in the symptomatic management of HD [95].

Loss of synapse and death of SPNs in HD has been linked to age-inappropriate expression of juvenile NMDARs containing GLuN3A subunits. GLuN3A promotes NMDA spiking by enhancing transmission across synapses in HD models [96].

Other medical therapies

Cysteamine: In a nuclear condensation cell toxicity assay, cysteamine exhibits a strong neuroprotective effect against toxicity caused by mHTT. It was also shown to safeguard mitochondrial structures harmful to mHTT. Neuroprotection by cysteamine in not mediated by cysteine metabolism. Certain metabolites of cysteamine like taurine and hypotaurine are neuroprotective against toxicity caused by HTT.

Cysteamine is known to activate secretion of BDNF. However, BDNF pathway antagonists could not protect cysteamine. The authors think more studies are required in this field to determine neuroprotective pathways [97]. Cysteamine has been demonstrated in numerous animal models of HD as potentially safe and effective [98].

A recent trial comprising of 96 patients with early-stage HD receiving 1200 mg delayed-release cysteamine bitartrate or placebo daily for 18 months was conducted. At the end of the study, the treatment effect was not statistically significant but less mean deterioration from baseline for the treated group as compared to placebo. The authors could not determine the efficacy of cysteamine in the studied population with HD but post hoc analyses indicated the need for future studies in large population subset [99].

Stem cell therapy

In HD, replacement of the degenerated striatal MSNs and reconstruction of damaged neural circuity is the main aim to reverse the disease or modify progression [100]. Modulation of glymphatic activity using IV-MSC can be a novel strategy for improving the potency of ASOs in the treatment of HD as delivering of ASOs to deeper brain structures is very difficult [101]. Recently Elbaz, et al. suggested combining LER/BM-MSC therapy seems to be superior to cell therapy alone in inhibiting 3-NP-induced neurological insults. This is mediated by modulation of two main signaling pathways i.e. Ca/CaN/NFATc4 and Wnt/β-catenin [102].

Yu, et al. demonstrated significantly ameliorated phenotypes of R6/2 mice after MSCs administration intranasally, suggesting this method can be effective delivering route of cells to the brain for HD therapy [103].

Cho, et al. demonstrated longer lifespans and improvement of motor function in HD mice (compared to a sham-injection group) that were grafted with NPCs derived from wild-type and HD monkeys plus NPCs expressing shRNA against HTT [104].

Eskandari, et al. implanted dental pulp stem cells (DPSCs) in 3-NP rat models of HD. The authors reported that DPSCs were able to survive and there was significant augmentation of muscle activity and motor skills. They also found out by histological analysis that treatment with DPSCs halted the shrinkage of striatum and in addition also inhibited gliosis and microgliosis in the striatum of 3-NP rat models. It was also shown that there was downregulation of caspase-3 and proinflammatory cytokines like IL-1β and TNF upon DPSCs grafting. The authors strongly believe that by grafting DPSCs two things can be achieved a) repairing of motor-skill impairment b) neurogenesis induction through secretion of neurotrophic factors and proper modulation of proinflammatory response [105].

Bayat, et al. in their study investigated the role of olfactory ecto-mesenchymals stem cells (OE-MSC) secretome in motor deficits caused by HD in a rat model. Bilateral intra-striatal implantation of OE-MSCs in the 3-NP + Cell group was done post 3-NP intraperitoneal injections. They found out striatal transplants of OE-MSCs reduced microglial inflammatory factor, TNFα in the 3-NP + Cell group, with a significant reduction in RIP3, the markers of necroptosis in striatum. There was a remarkable recovery of intrastriatal volume post grafting and the motor activities were enhanced in the 3-NP + cell group compared to the 3-NP + vehicle group [106].

Yoon, et al. investigated the therapeutic effects of NPCs derived from a human iPSC line (1231A3-NPCs) in the quinolinic acid (QA)-lesioned rat model of HD. 1231A3-NPCs were transplanted into the ipsilateral striatum 1 week after QA lesioning. They found out transplanted animals showed significant behavioral improvements for up to 12 weeks. Histological analysis showed transplanted 1231A3-NPCs also partially replaced the lost neurons in the striatum, enhanced endogenous neurogenesis, reduced inflammatory responses, and reconstituted the damaged neuronal connections [107].

Bessuso, et al. in their study showed in-vitro-differentiated human striatal progenitors undergo successful maturation and integrate into host circuits upon intra-striatal transplantation in a rat model of HD. The authors reported that the implanted grafts can directly communicate through synaptic contact with structures like globus pallidus, subthalmic nucleus, and substantia nigra. The transplanted subjects showed improvement of motor sensory tasks for up to 8 weeks post-transplant [108].

Carmela, et al. in their study used conditioned medium (CM-hAMSC) to treat R6/2 mouse model for HD. They found out those treated showed less severe signs of neurological dysfunction. Reduction in striatal atrophy and the formation of striatal neuronal intranuclear inclusion body was observed with a significant amelioration of brain pathology. Furthermore, BDNF levels was not significantly increased, along with decreased microglial activation, and inducible nitric oxide synthase levels. CM-hAMSC can act by modulating microglia and other inflammatory cells [109].

Recent study has reported that transplantation of 3D-derived striatal progenitors into a transgenic mouse model of HD slowed disease progression, improved motor coordination, and increased survival. The transplanted cells developed into a MSN like phenotype and synaptic connections was formed with the host cells [110].

Ebrahimi, et al. evaluated the in vitro and in vivo efficacy of umbilical cord matrix stem cells (UCMSCs) and their paracrine effect against oxidative stress with a specific focus on HD subjects. Initially, PC12 cells were exposed to superoxide in the presence of conditioned media (CM) collected from UCMSC (UCMSC-CM) and cell viability plus neuritogenesis were measured. After that bilateral striatal transplantation of UCMSC in 3-nitropropionic acid (3-NP) lesioned rat models was done, and post-graft analysis was performed after 1 month. They reported CM of UCMSC protected PC12 cells against oxidative stress and considerably enhanced neurite outgrowth and cell viability. Furthermore, transplanted UCMSC survived, gliosis was decreased, and amelioration of motor-coordination and muscle activity was seen, along with an increase in striatal volume as well as in dendritic length of the striatum in HD rats [111].

Deep brain stimulation

Deep brain stimulation (DBS) of the GPi shows good clinical efficacy in HD individuals as pathophysiologic disease mechanism in HD is related to the output from the GPi. Chorea-dominant HD and other subtypes such as dystonia may differ in spectral patterns in GPi. Elevated high-beta and gamma band activities are more likely to chorea specific. LFP (Local field potential) measures may help us to understand the abnormalities in basal ganglia signaling which may underlie HD symptoms. This could be considered as an useful biomarker for setting adaptive DBS parameters [112].

However, Ferrea and colleagues reported Gp-DBS in jHD is not generally recommended because no significant motor improvement was found when patients were followed up for 12 months [113].

Zittel and colleagues, prospectively evaluated the effects of bilateral DBS of GPi over one year in six severely affected HD subjects with chorea refractory to standard treatment in an advanced stage of the disease. They also evaluated the effects of GPi-DBS on the motor part of UHDRS, dystonia, bradykinesia, cognitive and psychiatric symptoms, and functional impairment hampering quality of life. The chorea sub-score significantly reduced postoperatively at 6 and 12 months, whereas UDHRS total motor score was significantly reduced at 6 months postoperatively, but overall effects did not sustain over 12 months. Pallidal DBS did not improve functional impairment or other motor symptoms. No effect was seen in psychiatric and cognitive symptoms. Three patients also developed severe spasticity during the follow up period. The authors suggest pallidal DBS could be a treatment option for HD patients with severe pharmacologically refractory chorea [114].

Gonzalez, et al. performed a prospective, open-label study of seven HD patients who underwent GPi DBS with median 3 year follow up. Results revealed a significant reduction of chorea (but not bradykinesia or dystonia) with off-stimulation evaluations confirming a persistent therapeutic effect of DBS [115].

A prospective, randomized, controlled, double-blind study evaluated six HD patients (including two juvenile HD) for equivalence of GPi and GPe stimulation. This study also had an open-label, 6-month follow up to assess chronic treatment effects. Chorea, quality-of-life, and disability scores improved significantly. However, there was no improvement in dystonia, and cognition remained stable. Both GPi and GPe were equal in terms of overall efficacy [116].

A meta-analysis by Yin, et al. found out GPi-DBS significantly improved the UHDRS-motor score in < 3 months, 3-9 months, and 9-12 months but did not continue in the later follow-up period. Clinically significant improvement in the UDHRS-chorea was seen in patients who were followed up for > 30 months. However, functional assessment did not improve 12 months post-operatively. The Westphal variant of HD (W-HD) did not show any motor benefits 6 months postoperatively. The authors also found out the only risk factor for DBS efficacy was the Westphal variant. The rate of stimulation- associated adverse events was quite high [117].

Sanrey, et al. looked at cognitive progression in HD patients with Continuous Electrical Neuromodulation (CEN) of the GPi with a follow up period of 5 years. Global cognitive profile of HD subjects treated with CEN was stable during the first 3 years of treatment. They also reported that chorea decreased post-operatively with a mean improvement of only 56% despite progession of the disease over time [118].

New developments

Lee, et al. in their study used exosomes as a messenger during heterochromic parabiosis for improvement of HD symptoms in R6/2 mice model [119]. Drew, et al. designed a cohort of minimum 18 patients in which 5 eligible patients will be randomly selected to undergo transplantation of 12-22 million foetal cells in a dose escalation paradigm. This delivery will enable the safety, acceptability, feasibility, and cost-effectiveness in foetal cell transplants in people with HD [120].

In summary, there has been extensive research on HD in recent years. Several methods and therapies are currently in development and lot of trials are ongoing in preclinical and human model side by side to address the etiology, pathophysiologic mechanisms, and modes of progression of this disease.

Disclosure

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript.

Special thanks to my supervisor Professor Dr. Hui Fang Shang who gave initial ideas and supported me through this research study. I would also like to thank Dr. Swatilekha Roy Sarkar for her valuable feedback on the manuscript and PubMed literature screening.

1. Bates GP, Dorsey R, Gusella JF, Hayden MR, Kay C, et al. Huntington disease. Nat Rev Dis Primers. 2015; 1: 15005. PubMed: https://pubmed.ncbi.nlm.nih.gov/27188817/
2. Finkbeiner S. Huntington's Disease. Cold Spring Harb Perspect Biol. 2011; 3: a007476. PubMed: https://pubmed.ncbi.nlm.nih.gov/21441583/
3. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. The Huntington's Disease Collaborative Research Group. Cell. 1993 Mar 26; 72: 971-983. PubMed: https://pubmed.ncbi.nlm.nih.gov/8458085/
4. Walker FO. Huntington's disease. Lancet. 2007 Jan 20; 369: 218-228. PubMed: https://pubmed.ncbi.nlm.nih.gov/17240289/
5. Gilliam TC, Tanzi RE, Haines JL, Bonner TI, Faryniarz AG, et al. Localization of the Huntington's disease gene to a small segment of chromosome 4 flanked by D4S10 and the telomere. Cell. 1987; 50: 565-571. PubMed: https://pubmed.ncbi.nlm.nih.gov/2886227/
6. Ghosh R, Tabrizi SJ. Huntington disease. Handb Clin Neurol. 2018; 147: 255-278. PubMed: https://pubmed.ncbi.nlm.nih.gov/29325616/
7. Lee JM, Ramos EM, Lee JH, Gillis T, Mysore JS, et al. CAG repeat expansion in Huntington disease determines age at onset in a fully dominant fashion. Neurology. 2012; 78: 690-695. PubMed: https://pubmed.ncbi.nlm.nih.gov/22323755/
8. Rubinsztein DC, Leggo J, Coles R, Almqvist E, Biancalana V, et al. Phenotypic characterization of individuals with 30-40 CAG repeats in the Huntington disease (HD) gene reveals HD cases with 36 repeats and apparently normal elderly individuals with 36-39 repeats. Am J Hum Genet. 1996; 59: 16-22. PubMed: https://pubmed.ncbi.nlm.nih.gov/8659522/
9. Kremer B, Almqvist E, Theilmann J, Spence N, Telenius H, et al. Sex-dependent mechanisms for expansions and contractions of the CAG repeat on affected Huntington disease chromosomes. Am J Hum Genet. 1995; 57: 343-350. PubMed: https://pubmed.ncbi.nlm.nih.gov/7668260/
10. Ranen NG, Stine OC, Abbott MH, Sherr M, Codori AM, et al. Anticipation and instability of IT-15 (CAG)n repeats in parent-offspring pairs with Huntington disease. Am J Hum Genet. 1995; 57: 593-602. PubMed: https://pubmed.ncbi.nlm.nih.gov/7668287/
11. Trottier Y, Biancalana V, Mandel JL. Instability of CAG repeats in Huntington's disease: relation to parental transmission and age of onset. J Med Genet. 1994; 31: 377-382. PubMed: https://pubmed.ncbi.nlm.nih.gov/8064815/
12. Myers RH, MacDonald ME, Koroshetz WJ, Duyao MP, Ambrose CM, et al. De novo expansion of a (CAG)n repeat in sporadic Huntington's disease. Nat Genet. 1993; 5: 168-173. PubMed: https://pubmed.ncbi.nlm.nih.gov/8252042/
13. Semaka A, Creighton S, Warby S, Hayden MR. Predictive testing for Huntington disease: interpretation and significance of intermediate alleles. Clin Genet. 2006; 70: 283-294. PubMed: https://pubmed.ncbi.nlm.nih.gov/16965319/
14. Andrew SE, Goldberg YP, Kremer B, Telenius H, Theilmann J, et al. The relationship between trinucleotide (CAG) repeat length and clinical features of Huntington's disease. Nat Genet. 1993; 4: 398-403. PubMed: https://pubmed.ncbi.nlm.nih.gov/8401589/
15. Genetic Modifiers of Huntington’s Disease (GeM-HD) Consortium. Identification of Genetic Factors that Modify Clinical Onset of Huntington's Disease. Cell. 2015; 162: 516-526. PubMed: https://pubmed.ncbi.nlm.nih.gov/26232222/
16. Rawlins MD, Wexler NS, Wexler AR, Tabrizi SJ, Douglas I, et al. The prevalence of huntington’s disease. Neuroepidemiology. 2016; 46: 144–153. PubMed: https://pubmed.ncbi.nlm.nih.gov/26824438/
17. Pringsheim T, Wiltshire K, Day L, Dykeman J, Steeves T, et al. The incidence and prevalence of huntington’s disease: a systematic review and meta-analysis. Mov Disord. 2012; 27: 1083–1091. PubMed: https://pubmed.ncbi.nlm.nih.gov/22692795/
18. Bashir H, Jankovic J. Treatment options for chorea. Expert Rev Neurother. 2018; 18: 51–63. PubMed: https://pubmed.ncbi.nlm.nih.gov/29120264/
19. Zuccato C, Valenza M, Cattaneo E. Molecular mechanisms and potential therapeutical targets in huntington’s disease. Physiol Rev.2010; 90: 905–981. PubMed: https://pubmed.ncbi.nlm.nih.gov/20664076/
20. Arrasate M, Finkbeiner S. Protein aggregates in huntington’s disease. Exp Neurol. 2012; 238: 1–11. PubMed: https://pubmed.ncbi.nlm.nih.gov/22200539/
21. Neueder A, Landles C, Ghosh R, Howland D, Myers RH, et al. The pathogenic exon 1 HTT protein is produced by incomplete splicing in huntington’s disease patients. Sci Rep. 2017; 7: 1307. PubMed: https://pubmed.ncbi.nlm.nih.gov/28465506/
22. Slow EJ, van Raamsdonk J, Rogers D, Coleman SH, Graham RK, et al. Selective striatal neuronal loss in a YAC128 mouse model of Huntington disease. Hum Mol Genet. 2003; 12: 1555–1567. PubMed: https://pubmed.ncbi.nlm.nih.gov/12812983/
23. Slow EJ, Graham RK, Osmand AP, Devon RS, Lu G, et al. Absence of behavioral abnormalities and neurodegeneration in vivo despite widespread neuronal huntingtin inclusions. Proc Natl Acad Sci U S A. 2005; 102: 11402–11407. PubMed: https://pubmed.ncbi.nlm.nih.gov/16076956/
24. Sica RE. Could astrocytes be the primary target of an offending agent causing the primary degenerative diseases of the human central nervous system? A hypothesis. Med Hypotheses. 2015; 84: 481–489. PubMed: https://pubmed.ncbi.nlm.nih.gov/25697116/
25. Fjodorova M, Louessard M, Li Z, De La Fuente DC, Dyke E, et al. CTIP2-Regulated Reduction in PKA-Dependent DARPP32 Phosphorylation in Human Medium Spiny Neurons: Implications for Huntington Disease. Stem Cell Reports. 2019; 13: 448-457. PubMed: https://pubmed.ncbi.nlm.nih.gov/31447328/
26. Wild EJ, Tabrizi SJ. Therapies targeting DNA and RNA in Huntington's disease [published correction appears in Lancet Neurol. 2017 Dec; 16: 954]. Lancet Neurol. 2017; 16: 837-847. PubMed: https://pubmed.ncbi.nlm.nih.gov/28920889/
27. Crooke ST. Molecular Mechanisms of Antisense Oligonucleotides. Nucleic Acid Ther. 2017; 27: 70-77. PubMed: https://pubmed.ncbi.nlm.nih.gov/28080221/
28. Du L, Kayali R, Bertoni C, Fike F, Hu H, et al. Arginine-rich cell-penetrating peptide dramatically enhances AMO-mediated ATM aberrant splicing correction and enables delivery to brain and cerebellum. Hum Mol Genet 2011; 20: 3151–3160. PubMed: https://pubmed.ncbi.nlm.nih.gov/21576124/
29. Aguiar S, van der Gaag B, Cortese FAB. RNAi mechanisms in Huntington's disease therapy: siRNA versus shRNA. Transl Neurodegener. 2017; 6: 30. PubMed: https://pubmed.ncbi.nlm.nih.gov/29209494/
30. Pfister EL, DiNardo N, Mondo E, Borel F, Conroy F, et al. Artificial miRNAs Reduce Human Mutant Huntingtin Throughout the Striatum in a Transgenic Sheep Model of Huntington's Disease. Hum Gene Ther. 2018; 29: 663-673. PubMed: https://pubmed.ncbi.nlm.nih.gov/29207890/
31. Sah DW, Aronin N. Oligonucleotide therapeutic approaches for Huntington disease. J Clin Invest. 2011; 121: 500-507. PubMed: https://pubmed.ncbi.nlm.nih.gov/21285523/
32. Boudreau RL, McBride JL, Martins I, Shen S, Xing Y, et al. Nonallele-specific silencing of mutant and wild-type huntingtin demonstrates therapeutic efficacy in Huntington’s disease mice. Mol Ther. 2009; 17: 1053–1063. PubMed: https://pubmed.ncbi.nlm.nih.gov/19240687/
33. McBride JL, Pitzer MR, Boudreau RL, Dufour B, Hobbs T, et al. Preclinical safety of RNAi mediated HTT suppression in the rhesus macaque as a potential therapy for Huntington’s disease. Mol Ther. 2011; 19: 2152–2162. PubMed: https://pubmed.ncbi.nlm.nih.gov/22031240/
34. Qu Y, Liu Y, Noor AF, Tran J, Li R. Characteristics and advantages of adeno-associated virus vector-mediated gene therapy for neurodegenerative diseases. Neural Regen Res. 2019; 14: 931-938. PubMed: https://pubmed.ncbi.nlm.nih.gov/30761996/
35. Merkel SF, Andrews AM, Lutton EM, Mu D, Hudry E, et al. Trafficking of adeno-associated virus vectors across a model of the blood-brain barrier; a comparative study of transcytosis and transduction using primary human brain endothelial cells. J Neurochem. 2017; 140: 216-230. PubMed: https://pubmed.ncbi.nlm.nih.gov/27718541/
36. Dufour BD, Smith CA, Clark RL, Walker TR, McBride JL. Intrajugular vein delivery of AAV9-RNAi prevents neuropathological changes and weight loss in huntington’s disease mice. Mol Ther. 2014; 22: 797–810. PubMed: https://pubmed.ncbi.nlm.nih.gov/24390280/
37. Matsuzaki Y, Konno A, Mochizuki R, Shinohara Y, Nitta K, et al. Intravenous administration of the adeno-associated virus-PHP.B. capsid fails to upregulate transduction efficiency in the marmoset brain. Neurosci Lett. 2018; 665: 182–188. PubMed: https://pubmed.ncbi.nlm.nih.gov/29175632/
38. Marco S, Murillo A, Pérez-Otaño I. RNAi-Based GluN3A Silencing Prevents and Reverses Disease Phenotypes Induced by Mutant huntingtin. Mol Ther. 2018; 26: 1965-1972. PubMed: https://pubmed.ncbi.nlm.nih.gov/29914757/
39. Matthes F, Massari S, Bochicchio A, Schorpp K, Schilling J, et al. Reducing Mutant Huntingtin Protein Expression in Living Cells by a Newly Identified RNA CAG Binder. ACS Chem Neurosci. 2018; 9: 1399-1408. PubMed: https://pubmed.ncbi.nlm.nih.gov/29506378/
40. Sava V, Fihurka O, Khvorova A, Sanchez-Ramos J. Enriched chitosan nanoparticles loaded with siRNA are effective in lowering Huntington's disease gene expression following intranasal administration. Nanomedicine. 2020; 24: 102119. PubMed: https://pubmed.ncbi.nlm.nih.gov/31666200/
41. Miniarikova J, Zimmer V, Martier R, Brouwers CC, Pythoud C, et al. AAV5-miHTT gene therapy demonstrates suppression of mutant huntingtin aggregation and neuronal dysfunction in a rat model of Huntington's disease. Gene Ther. 2017; 24: 630-639. PubMed: https://pubmed.ncbi.nlm.nih.gov/28771234/
42. Keskin S, Brouwers CC, Sogorb-Gonzalez M, Martier R, Depla JA, et al. AAV5-miHTT Lowers Huntingtin mRNA and Protein without Off-Target Effects in Patient-Derived Neuronal Cultures and Astrocytes. Mol Ther Methods Clin Dev. 2019; 15: 275-284. PubMed: https://pubmed.ncbi.nlm.nih.gov/31737741/
43. Rinaldi C, Wood MJA. Antisense oligonucleotides: the next frontier for treatment of neurological disorders. Nat Rev Neurol.2017; 14: 9–21. PubMed: https://pubmed.ncbi.nlm.nih.gov/29192260/
44. Ionis Pharmaceuticals. IONIS-HTT Rx (RG6042) top-line data demonstrate significant reductions of disease-causing mutant huntingtin protein in people with huntington’s disease. 2019. http://ir.ionispharma.com/node/23401/pdf
45. Datson NA, González-Barriga A, Kourkouta E, Weij R, van de Giessen J, et al. The expanded CAG repeat in the huntingtin gene as target for therapeutic RNA modulation throughout the HD mouse brain. PLoS One. 2017; 12: e0171127. PubMed: https://pubmed.ncbi.nlm.nih.gov/28182673/
46. Keeler AM, Sapp E, Chase K, Sottosanti E, Danielson E, et al. Cellular Analysis of Silencing the Huntington's Disease Gene Using AAV9 Mediated Delivery of Artificial Micro RNA into the Striatum of Q140/Q140 Mice. J Huntingtons Dis. 2016; 5: 239-248. PubMed: https://pubmed.ncbi.nlm.nih.gov/27689620/
47. Mathkar PP, Suresh D, Dunn J, Tom CM, Mattis VB. Characterization of Neurodevelopmental Abnormalities in iPSC-Derived Striatal Cultures from Patients with Huntington's Disease. J Huntingtons Dis. 2019; 8: 257-269. PubMed: https://pubmed.ncbi.nlm.nih.gov/31381521/
48. Geary RS, Norris D, Yu R, Bennett CF. Pharmacokinetics, biodistribution and cell uptake of antisense oligonucleotides. Adv Drug Deliv Rev.2015; 87: 46–51. PubMed: https://pubmed.ncbi.nlm.nih.gov/25666165/
49. Kim MS, Kini AG. Engineering and Application of Zinc Finger Proteins and TALEs for Biomedical Research. Mol Cells. 2017; 40: 533-541. PubMed: https://pubmed.ncbi.nlm.nih.gov/28835021/
50. Mittelman D, Moye C, Morton J, Sykoudis K, Lin Y, et al. Zinc-finger directed double-strand breaks within CAG repeat tracts promote repeat instability in human cells. Proc Natl Acad Sci U S A. 2009; 106: 9607–9612. PubMed: https://pubmed.ncbi.nlm.nih.gov/19482946/
51. Garriga-Canut M, Agustín-Pavón C, Herrmann F, Sánchez A, Dierssen M, et al. Synthetic zinc finger repressors reduce mutant huntingtin expression in the brain of R6/2 mice. Proc Natl Acad Sci U S A. 2012; 109: E3136–45. PubMed: https://pubmed.ncbi.nlm.nih.gov/23054839/
52. Cubbon A, Ivancic-Bace I, Bolt EL. CRISPR-Cas immunity, DNA repair and genome stability. Biosci Rep. 2018; 38: BSR20180457. PubMed: https://pubmed.ncbi.nlm.nih.gov/30209206/
53. Pickar-Oliver A, Gersbach CA. The next generation of CRISPR-Cas technologies and applications. Nat Rev Mol Cell Biol. 2019; 20: 490-507. PubMed: https://pubmed.ncbi.nlm.nih.gov/31147612/
54. Nambiar TS, Billon P, Diedenhofen G, Hayward SB, Taglialatela A, et al. Stimulation of CRISPR-mediated homology-directed repair by an engineered RAD18 variant. Nat Commun. 2019; 10: 3395. PubMed: https://pubmed.ncbi.nlm.nih.gov/31363085/
55. Yang S, Chang R, Yang H, Zhao T, Hong Y, et al. CRISPR/Cas9-mediated gene editing ameliorates neurotoxicity in mouse model of huntington’s disease. J Clin Invest. 2017; 127: 2719–2724. PubMed: https://pubmed.ncbi.nlm.nih.gov/28628038/
56. Shin JW, Kim KH, Chao MJ, Atwal RS, Gillis T, et al. Permanent inactivation of Huntington's disease mutation by personalized allele-specific CRISPR/Cas9. Hum Mol Genet. 2016; 25: 4566-4576. PubMed: https://pubmed.ncbi.nlm.nih.gov/28172889/
57. Pan Y, Daito T, Sasaki Y, Chung YH, Xing X, et al. Inhibition of DNA Methyltransferases Blocks Mutant Huntingtin-Induced Neurotoxicity. Sci Rep. 2016; 21: 33766. PubMed: https://pubmed.ncbi.nlm.nih.gov/27649847/
58. Luthi-Carter R, Taylor DM, Pallos J, Lambert E, Amore A, et al. SIRT2 inhibition achieves neuroprotection by decreasing sterol biosynthesis. Proc Natl Acad Sci USA. 2010; 107: 7927–7932. PubMed: https://pubmed.ncbi.nlm.nih.gov/20378838/
59. Zuccato C, Valenza M, Cattaneo E. Molecular mechanisms and potential therapeutical targets in Huntington’s disease. Physiol Rev. 2010; 90: 905–981. PubMed: https://pubmed.ncbi.nlm.nih.gov/20664076/
60. Chopra V, Quinti L, Kim J, Vollor L, Narayanan KL, et al. The sirtuin 2 inhibitor AK-7 is neuroprotective in Huntington's disease mouse models. Cell Rep. 2012; 2: 1492-1497. PubMed: https://pubmed.ncbi.nlm.nih.gov/23200855/
61. Jeong H, Then F, Melia TJ Jr, Mazzulli JR, Cui L, et al. Acetylation targets mutant huntingtin to autophagosomes for degradation. Cell 2009; 137: 60–72. PubMed: https://pubmed.ncbi.nlm.nih.gov/19345187/
62. Zhang F, Wang S, Gan L, Vosler PS, Gao Y, et al. Protective effects and mechanisms of sirtuins in the nervous system. Prog Neurobiol 2011; 95: 373–395. PubMed: https://pubmed.ncbi.nlm.nih.gov/21930182/
63. Pallos J, Bodai L, Lukacsovich T, Purcell JM, Steffan JS, et al. Inhibition of specific HDACs and sirtuins suppresses pathogenesis in a Drosophila model of Huntington’s disease. Hum Mol Genet 2008; 17: 3767–3775. PubMed: https://pubmed.ncbi.nlm.nih.gov/18762557/
64. Napper AD, Hixon J, McDonagh T, Keavey K, Pons JP, et al. Discovery of indoles as potent and selective inhibitors of the deacetylase SirT1. J Med Chem 2005; 48: 8045–854. PubMed: https://pubmed.ncbi.nlm.nih.gov/16335928/
65. Smith MR, Syed A, Lukacsovich T, Purcell J, Barbaro BA, et al. Sirtuin 1 inhibition alleviates pathology in multiple animal and cell models of Huntington’s disease. Hum Mol Genet 2014; 23: 2995–3007. PubMed: https://pubmed.ncbi.nlm.nih.gov/24436303/
66. Reilmann R, Squitieri F, Priller J, et al. N02 Safety And Tolerability Of Selisistat For The Treatment Of Huntington’s Disease: Results From A Randomised, Double-blind, Placebo-controlled Phase Ii Trial. J Neurol Neurosurg Psychiatry. 2014; 85: A102.
67. Deb A, Frank S, Testa CM. New symptomatic therapies for Huntington disease. Handb Clin Neurol. 2017; 144: 199-207. PubMed: https://pubmed.ncbi.nlm.nih.gov/28947118/
68. Johanssen T, Suphantarida N, Donnelly PS, Liu XM, Petrou S, et al. PBT2 inhibits glutamate-induced excitotoxicity in neurons through metal-mediated preconditioning. Neurobiol Dis. 2015; 81: 176-185. PubMed: https://pubmed.ncbi.nlm.nih.gov/25697105/
69. Huntington Study Group Reach 2HD Investigators. Safety, tolerability, and efficacy of PBT2 in huntington’s disease: a phase 2, randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2015; 14: 39–47. PubMed: https://pubmed.ncbi.nlm.nih.gov/25467848/
70. Prana Biotech. 2015. FDA end of phase 2 status update. 2019. http://pranabio.com/wp-content/uploads/2015/02/150213_FDA-notification-FINAL.pdf
71. Rocha NP, Ribeiro FM, Furr-Stimming E, Teixeira AL. Neuroimmunology of Huntington's Disease: Revisiting Evidence from Human Studies. Mediators Inflamm. 2016; 2016: 8653132. PubMed: https://pubmed.ncbi.nlm.nih.gov/27578922/
72. Crotti A, Benner C, Kerman BE, Gosselin D, Lagier-Tourenne C, et al. Mutant huntingtin promotes autonomous microglia activation via myeloid lineage-determining factors. Nat Neurosci. 2014; 17: 513–521. PubMed: https://pubmed.ncbi.nlm.nih.gov/24584051/
73. Garcia-Miralles M, Yusof NABM, Tan JY, Radulescu CI, Sidik H, et al. Laquinimod Treatment Improves Myelination Deficits at the Transcriptional and Ultrastructural Levels in the YAC128 Mouse Model of Huntington Disease. Mol Neurobiol. 2019; 56: 4464-4478. PubMed: https://pubmed.ncbi.nlm.nih.gov/30334188/
74. Ellrichmann G, Blusch A, Fatoba O, Brunner J, Reick C, et al. Laquinimod treatment in the R6/2 mouse model Sci Rep. 2017; 7: 4947. PubMed: https://pubmed.ncbi.nlm.nih.gov/28694434/
75. Garcia-Miralles M, Hong X, Tan LJ, Caron NS, Huang Y, et al. Laquinimod rescues striatal, cortical and white matter pathology and results in modest behavioural improvements in the YAC128 model of Huntington disease. Sci Rep. 2016; 6: 31652. PubMed: https://pubmed.ncbi.nlm.nih.gov/27528441/
76. Ehrnhoefer DE, Caron NS, Deng Y, Qiu X, Tsang M, et al. Laquinimod decreases Bax expression and reduces caspase-6 activation in neurons. Exp Neurol. 2016; 283: 121-128. PubMed: https://pubmed.ncbi.nlm.nih.gov/27296315/
77. Rodrigues FB, Wild EJ. Huntington's Disease Clinical Trials Corner: August 2018. J Huntingtons Dis. 2018; 7: 279-286. PubMed: https://pubmed.ncbi.nlm.nih.gov/30103342/
78. Rodrigues FB, Ferreira JJ, Wild EJ. Huntington's Disease Clinical Trials Corner: June 2019. J Huntingtons Dis. 2019; 8: 363-371. PubMed: https://pubmed.ncbi.nlm.nih.gov/31381524/
79. https://huntingtonsdiseasenews.com/2018/04/26/aan2018-phase-2-trial-targets-loss-brain-volume-huntingtons/
80. Jimenez-Sanchez M, Licitra F, Underwood BR, Rubinsztein DC. Huntington's Disease: Mechanisms of Pathogenesis and Therapeutic Strategies. Cold Spring Harb Perspect Med. 2017; 7: a024240. PubMed: https://pubmed.ncbi.nlm.nih.gov/27940602/
81. Sahlholm K, Århem P, Fuxe K, Marcellino D. The dopamine stabilizers ACR16 and (-)-OSU6162 display nanomolar affinities at the σ-1 receptor. Mol Psychiatry. 2013; 18: 12-14. PubMed: https://pubmed.ncbi.nlm.nih.gov/22349783/
82. Waters S, Tedroff J, Ponten H, Klamer D, Sonesson C, et al. Pridopidine: Overview of Pharmacology and Rationale for its Use in Huntington's Disease. J Huntingtons Dis. 2018; 7: 1-16. PubMed: https://pubmed.ncbi.nlm.nih.gov/29480206/
83. Tang TS, Slow E, Lupu V, Stavrovskaya IG, Sugimori M, et al. Disturbed Ca2+ signaling and apoptosis of medium spiny neurons in huntington’s disease. Proc Natl Acad Sci USA. 2005; 102: 2602–2607. PubMed: https://pubmed.ncbi.nlm.nih.gov/15695335/
84. Hyrskyluoto A, Pulli I, Törnqvist K, Ho TH, Korhonen L, et al. Sigma-1 receptor agonist PRE084 is protective against mutant huntingtin-induced celldegeneration: involvement of calpastatin and the NF-κB pathway.Cell Death Dis. 2013; 4: e646. PubMed: https://pubmed.ncbi.nlm.nih.gov/23703391/
85. Smith-Dijak AI, Nassrallah WB, Zhang LYJ, Geva M, Hayden MR, et al. Impairment and Restoration of Homeostatic Plasticity in Cultured Cortical Neurons From a Mouse Model of Huntington Disease. Front Cell Neurosci. 2019; 13: 209. PubMed: https://pubmed.ncbi.nlm.nih.gov/31156395/
86. Eddings CR, Arbez N, Akimov S, Geva M, Hayden MR, et al. Pridopidine protects neurons from mutant-huntingtin toxicity via the sigma-1 receptor. Neurobiology of Disease. 2019; 129; 118–129. PubMed: https://pubmed.ncbi.nlm.nih.gov/31108174/
87. Kusko R, Dreymann J, Ross J, et al. Large-scale transcriptomic analysis reveals that pridopidine reverses aberrant gene expression and activates neuroprotective pathways in the YAC128 HD mouse. Mol Neurodegener. 2018; 13: 25.
88. Garcia-Miralles M, Geva M, Tan JY, Mohammad Yusof NABM, Cha Y, et al. Early pridopidine treatment improves behavioral and transcriptional deficits in YAC128 Huntington disease mice. JCI Insight. 2017; 2: e95665. PubMed: https://pubmed.ncbi.nlm.nih.gov/29212949/
89. Reilmann R, McGarry A, Grachev ID, et al. Safety and efficacy of pridopidine in patients with Huntington's disease (PRIDE-HD): a phase 2, randomised, placebo-controlled, multicentre, dose-ranging study. Lancet Neurol. 2019; 18: 165-176. PubMed: https://pubmed.ncbi.nlm.nih.gov/30563778/
90. Jokinen EM, Postila PA, Ahinko M, Niinivehmas S, Pentikäinen OT. Fragment- and negative image-based screening of phosphodiesterase 10A inhibitors. Chem Biol Drug Des. 2019; 94: 1799-1812. PubMed: https://pubmed.ncbi.nlm.nih.gov/31260165/
91. Diggle CP, Sukoff Rizzo SJ, Popiolek M, et al. Biallelic Mutations in PDE10A Lead to Loss of Striatal PDE10A and a Hyperkinetic Movement Disorder with Onset in Infancy. Am J Hum Genet. 2016; 98: 735-743. PubMed: https://pubmed.ncbi.nlm.nih.gov/27058446/
92. Harada A, Suzuki K, Kimura H. TAK-063, a Novel Phosphodiesterase 10A Inhibitor, Protects from Striatal Neurodegeneration and Ameliorates Behavioral Deficits in the R6/2 Mouse Model of Huntington's Disease. J Pharmacol Exp Ther. 2017; 360: 75-83.
93. Beaumont V, Zhong S, Lin H, Hinttala R, Schülke JP, et al. Phosphodiesterase 10A Inhibition Improves Cortico-Basal Ganglia Function in Huntington's Disease Models. Neuron. 2016; 92: 1220-1237.
94. Chang WT, Puspitasari F, Garcia-Miralles M, Yeow LY, Tay HC, et al. Connectomic imaging reveals Huntington-related pathological and pharmaceutical effects in a mouse model. NMR Biomed. 2018; 31: e4007. PubMed: https://pubmed.ncbi.nlm.nih.gov/30260561/
95. Chidambaram SB, Vijayan R, Sekar S, Mani S, Rajamani B, et al. Simultaneous blockade of NMDA receptors and PARP-1 activity synergistically alleviate immunoexcitotoxicity and bioenergetics in 3-nitropropionic acid intoxicated mice: Evidences from memantine and 3-aminobenzamide interventions. Eur J Pharmacol. 2017; 803: 148-158. PubMed: https://pubmed.ncbi.nlm.nih.gov/28322842/
96. Mahfooz K, Marco S, Martínez-Turrillas R, Raja MK, Pérez-Otaño I, et al. GluN3A promotes NMDA spiking by enhancing synaptic transmission in Huntington's disease models. Neurobiol Dis. 2016; 93: 47-56. PubMed: https://pubmed.ncbi.nlm.nih.gov/27072890/
97. Arbez N, Roby E, Akimov S, Eddings C, Ren M, et al. Cysteamine Protects Neurons from Mutant Huntingtin Toxicity. J Huntingtons Dis. 2019; 8: 129-143. PubMed: https://pubmed.ncbi.nlm.nih.gov/30856117/
98. Borrell-Pagès M, Canals JM, Cordelières FP, Parker JA, Pineda JR, et al. Cystamine and cysteamine increase brain levels of BDNF in Huntington disease via HSJ1b and transglutaminase. J Clin Invest. 2006; 116: 1410-1424. PubMed: https://pubmed.ncbi.nlm.nih.gov/16604191/
99. Verny C, Bachoud-Lévi AC, Durr A, Goizet C, Azulay JP, et al. A randomized, double-blind, placebo-controlled trial evaluating cysteamine in Huntington's disease. Mov Disord. 2017; 32: 932-936. PubMed: https://pubmed.ncbi.nlm.nih.gov/28436572/
100. Colpo GD, Ascoli BM, Wollenhaupt-Aguiar B, Pfaffenseller B, Silva EG, et al. Mesenchymal stem cells for the treatment of neurodegenerative and psychiatric disorders. An Acad Bras Cienc. 2015; 87: 1435–1449. PubMed: https://pubmed.ncbi.nlm.nih.gov/26247151/
101. Wu TT, Su FJ, Feng YQ, Liu B, Li MY, et al. Mesenchymal stem cells alleviate AQP-4-dependent glymphatic dysfunction and improve brain distribution of antisense oligonucleotides in BACHD mice. Stem Cells. 2020; 38: 218-230. PubMed: https://pubmed.ncbi.nlm.nih.gov/31648394/
102. Elbaz EM, Helmy HS, El-Sahar AE, Saad MA, Sayed RH. Lercanidipine boosts the efficacy of mesenchymal stem cell therapy in 3-NP-induced Huntington's disease model rats via modulation of the calcium/calcineurin/NFATc4 and Wnt/β-catenin signalling pathways. Neurochem Int. 2019; 131: 104548. PubMed: https://pubmed.ncbi.nlm.nih.gov/31539560/
103. Yu-Taeger L, Stricker-Shaver J, Arnold K, Bambynek-Dziuk P, Novati A, et al. Intranasal Administration of Mesenchymal Stem Cells Ameliorates the Abnormal Dopamine Transmission System and Inflammatory Reaction in the R6/2 Mouse Model of Huntington Disease. Cells. 2019; 8: 595. PubMed: https://pubmed.ncbi.nlm.nih.gov/31208073/
104. Cho IK, Hunter CE, Ye S, Pongos AL, Chan AWS. Combination of stem cell and gene therapy ameliorates symptoms in Huntington's disease mice. NPJ Regen Med. 2019; 4: 7. PubMed: https://pubmed.ncbi.nlm.nih.gov/30937182/
105. Eskandari N, Boroujeni ME, Abdollahifar MA, Piryaei A, Khodagholi F, et al. Transplantation of human dental pulp stem cells compensates for striatal atrophy and modulates neuro-inflammation in 3-nitropropionic acid rat model of Huntington's disease. 2020. Neurosci Res. 2020; S0168-0102(20)30505-8. PubMed: https://pubmed.ncbi.nlm.nih.gov/33359180/
106. Bayat AH, Saeidikhoo S, Ebrahimi V, Mesgar S, Joneidi M, et al. Bilateral striatal transplantation of human olfactory stem cells ameliorates motor function, prevents necroptosis-induced cell death and improves striatal volume in the rat model of Huntington's disease. J Chem Neuroanat. 2021; 112: 101903. PubMed: https://pubmed.ncbi.nlm.nih.gov/33278568/
107. Yoon Y, Kim HS, Hong CP, Li E, Jeon I, et al. Neural Transplants From Human Induced Pluripotent Stem Cells Rescue the Pathology and Behavioral Defects in a Rodent Model of Huntington's Disease. Front Neurosci. 2020; 14: 558204. PubMed: https://pubmed.ncbi.nlm.nih.gov/33071737/
108. Besusso D, Schellino R, Boido M, Belloli S, Parolisi R, et al. Stem Cell-Derived Human Striatal Progenitors Innervate Striatal Targets and Alleviate Sensorimotor Deficit in a Rat Model of Huntington Disease. Stem Cell Reports. 2020; 14: 876-891. PubMed: https://pubmed.ncbi.nlm.nih.gov/32302555/
109. Giampà C, Alvino A, Magatti M, Silini AR, Cardinale A, et al. Conditioned medium from amniotic cells protects striatal degeneration and ameliorates motor deficits in the R6/2 mouse model of Huntington's disease. J Cell Mol Med. 2019; 23: 1581-1592. PubMed: https://pubmed.ncbi.nlm.nih.gov/30585395/
110. Adil MM, Gaj T, Rao AT, Kulkarni RU, Fuentes CM, et al. hPSC-Derived Striatal Cells Generated Using a Scalable 3D Hydrogel Promote Recovery in a Huntington Disease Mouse Model. Stem Cell Reports. 2018; 10: 1481-1491. PubMed: https://pubmed.ncbi.nlm.nih.gov/29628395/
111. Ebrahimi MJ, Aliaghaei A, Boroujeni ME, Khodagholi F, Meftahi G, et al. Human Umbilical Cord Matrix Stem Cells Reverse Oxidative Stress-Induced Cell Death and Ameliorate Motor Function and Striatal Atrophy in Rat Model of Huntington Disease. Neurotox Res. 2018; 34: 273-284. PubMed: https://pubmed.ncbi.nlm.nih.gov/29520722/
112. Zhu G, Geng X, Tan Z, Chen Y, Zhang R, et al. Characteristics of Globus Pallidus Internus Local Field Potentials in Hyperkinetic Disease. Front Neurol. 2018; 9: 934. PubMed: https://pubmed.ncbi.nlm.nih.gov/30455666/
113. Ferrea S, Groiss SJ, Elben S, Hartmann CJ, Dunnett SB, et al. Pallidal deep brain stimulation in juvenile Huntington's disease: local field potential oscillations and clinical data. J Neurol. 2018; 265: 1573-1579. PubMed: https://pubmed.ncbi.nlm.nih.gov/29725840/
114. Zittel S, Tadic V, Moll CKE, Bäumer T, Fellbrich A, et al. Prospective evaluation of Globus pallidus internus deep brain stimulation in Huntington's disease. Parkinsonism Relat Disord. 2018; 51: 96-100. PubMed: https://pubmed.ncbi.nlm.nih.gov/29486999/
115. Gonzalez V, Cif L, Biolsi B, Seychelles A, Sanrey E, et al. Deep brain stimulation for Huntington’s disease: long-term results of a prospective open label study. J Neurosurg. 2014; 121: 114–122. PubMed: https://pubmed.ncbi.nlm.nih.gov/24702329/
116. Wojtecki L, Groiss SJ, Ferrea S, Elben S, Hartmann CJ, et al. A prospective pilot trial for pallidal deep brain stimulation in huntington’s disease. Front Neurol. 2015; 6: 177. PubMed: https://pubmed.ncbi.nlm.nih.gov/26347707/
117. Yin Z, Bai Y, Zhang H, Liu H, Hu W, et al. An individual patient analysis of the efficacy of using GPi-DBS to treat Huntington's disease. Brain Stimul. 2020; 13: 1722-1731. PubMed: https://pubmed.ncbi.nlm.nih.gov/33038596/
118. Sanrey E, Macioce V, Gonzalez V, Cif L, Cyprien F, et al. Does pallidal neuromodulation influence cognitive decline in Huntington's disease? J Neurol. 2021; 268: 613-622. PubMed: https://pubmed.ncbi.nlm.nih.gov/32886253/
119. Lee M, Im W, Kim M. Exosomes as a potential messenger unit during heterochronic parabiosis for amelioration of Huntington's disease. Neurobiol Dis. 2021; 155: 105374. PubMed: https://pubmed.ncbi.nlm.nih.gov/33940179/
120. Drew CJG, Sharouf F, Randell E, Brookes-Howell L, Smallman K, et al. Protocol for an open label: phase I trial within a cohort of foetal cell transplants in people with Huntington's disease. Brain Commun. 2021; 3: fcaa230. PubMed: https://pubmed.ncbi.nlm.nih.gov/33543141/