Therapeutic advances in neural regeneration for Huntington’s disease

Huntington’s disease is a neurodegenerative disease caused by the expansion mutation of a cytosine-adenine-guanine triplet in the exon 1 of the HTT gene which is responsible for the production of the huntingtin (Htt) protein. In physiological conditions, Htt is involved in many cellular processes such as cell signaling, transcriptional regulation, energy metabolism regulation, DNA maintenance, axonal trafficking, and antiapoptotic activity. When the genetic alteration is present, the production of a mutant version of Htt (mHtt) occurs, which is characterized by a plethora of pathogenic activities that, finally, lead to cell death. Among all the cells in which mHtt exerts its dangerous activity, the GABAergic Medium Spiny Neurons seem to be the most affected by the mHtt-induced excitotoxicity both in the cortex and in the striatum. However, as the neurodegeneration proceeds ahead the neuronal loss grows also in other brain areas such as the cerebellum, hypothalamus, thalamus, subthalamic nucleus, globus pallidus, and substantia nigra, determining the variety of symptoms that characterize Huntington’s disease. From a clinical point of view, Huntington’s disease is characterized by a wide spectrum of symptoms spanning from motor impairment to cognitive disorders and dementia. Huntington’s disease shows a prevalence of around 3.92 cases every 100,000 worldwide and an incidence of 0.48 new cases every 100,000/year. To date, there is no available cure for Huntington’s disease. Several treatments have been developed so far, aiming to reduce the severity of one or more symptoms to slow down the inexorable decline caused by the disease. In this context, the search for reliable strategies to target the different aspects of Huntington’s disease become of the utmost interest. In recent years, a variety of studies demonstrated the detrimental role of neuronal loss in Huntington’s disease condition highlighting how the replacement of lost cells would be a reasonable strategy to overcome the neurodegeneration. In this view, numerous have been the attempts in several preclinical models of Huntington’s disease to evaluate the feasibility of invasive and non-invasive approaches. Thus, the aim of this review is to offer an overview of the most appealing approaches spanning from stem cell-based cell therapy to extracellular vesicles such as exosomes in light of promoting neurogenesis, discussing the results obtained so far, their limits and the future perspectives regarding the neural regeneration in the context of Huntington’s disease.

Neuroimaging in Huntington's disease

Huntington's disease(HD) is a progressive and fatal neurodegenerative disorder caused by an expanded tri-nucleotide CAG sequence in huntingtin gene(HTT) on chromosome 4. HD manifests with chorea, cognitive and psychiatric symptoms. Although advances in genetics allow identification of individuals carrying the HD gene, much is still unknown about the mechanisms underly-ing the development of overt clinical symptoms and the transitional period between premanifestation and mani-festation of the disease. HD has no cure and patients rely only in symptomatic treatment. There is an urgent need to identify biomarkers that are able to monitor disease progression and assess the development and efficacy of novel disease modifying drugs. Over the past years, neuroimaging techniques such as magnetic resonance imaging(MRI) and positron emission tomog-raphy(PET) have provided important advances in our understanding of HD. MRI provides information about structural and functional organization of the brain, while PET can detect molecular changes in the brain. MRI and PET are able to detect changes in the brains of HD gene carriers years ahead of the manifestation of the dis-ease and have also proved to be powerful in assessingdisease progression. However, no single technique hasbeen validated as an optimal biomarker. An integrativemultimodal imaging approach, which combines differ-ent MRI and PET techniques, could be recommendedfor monitoring potential neuroprotective and preventivetherapies in HD. In this article we review the currentneuroimaging literature in HD.

Linguistic Characteristics of Mandarin-Speaking Huntington’s Disease Patients

Objective Linguistic problem is common in Huntington’s disease(HD)patients.It has been studied before in native speakers of alphabetic languages,such as English.As a hieroglyphic language,Chinese differs from alphabetic languages in terms of phonology,morphology,semantics and syntax.We aimed to investigate the linguistic characteristics of manifest HD in native speakers of Mandarin.Meanwhile,we expected to explore the linguistic differences associated with cortical or subcortical pathology.Methods Five HD patients and five Alzheimer’s disease(AD)patients matched in age,gender,disease course and educational level were enrolled.All the participants were Mandarin native speakers.All finished history inquiry,physical examination,basic test,genetic test and neuropsychological assessment.Language evaluation was performed by Aphasia Battery of Chinese.Results HD patients had a mean disease course of 5.4±2.97(range,2-10)years.They showed a linguistic disorder close to transcortical motor aphasia.They exhibited prominent phonological impairment,as well as slight semantic and syntactic abnormality.Tonic errors were found in speech.Character structural errors and substitutions were detected in writing.In comparison,AD patients showed a more severe linguistic impairment,characterized by global aphasia with more semantic errors.Conclusion Mandarin-speaking HD patients have a transcortical motor aphasia-like disturbance with prominent phonological impairment,whereas AD patients have a more severe global aphasia with salient semantic impairment.

Clinical trial perspective for adult and juvenile Huntington's disease using genetically-engineered mesenchymal stem cells

Progress to date from our group and others indicate that using genetically-engineered mesenchymal stem cells（MSC） to secrete brain-derived neurotrophic factor（BDNF） supports our plan to submit an Investigational New Drug application to the Food and Drug Administration for the future planned Phase 1 safety and tolerability trial of MSC/BDNF in patients with Huntington＇s disease（HD）. There are also potential applications of this approach beyond HD. Our biological delivery system for BDNF sets the precedent for adult stem cell therapy in the brain and could potentially be modified for other neurodegenerative disorders such as amyotrophic lateral sclerosis（ALS）, spinocerebellar ataxia（SCA）, Alzheimer＇s disease, and some forms of Parkinson＇s disease. The MSC/BDNF product could also be considered for studies of regeneration in traumatic brain injury, spinal cord and peripheral nerve injury. This work also provides a platform for our future gene editing studies, since we will again use MSCs to deliver the needed molecules into the central nervous system.

Promises and pitfalls of immune-based strategies for Huntington's disease

Huntington＇s disease （HD） is an autosomal-dominant neurodegenerative disease characterized by the selec- tive loss of neurons in the striatum and cortex, leading to progressive motor dysfunction, cognitive decline and behavioral symptoms. HD is caused by a trinucleotide （CAG） repeat expansion in the gene encoding for huntingtin. Several studies have suggested that inflammation is an important feature of HD and it is already observed in the early stages of the disease. Recently, new molecules presenting anti-inflammatory and/or immunomodulatory have been investigated for HD. The objective of this review is to discuss the data obtained so far on the immune-based therapeutic strategies for HD.

Altered microRNA expression in animal models of Huntington’s disease and potential therapeutic strategies

A review of recent animal models of Huntington’s disease showed many microRNAs had altered expression levels in the striatum and cerebral cortex,and which were mostly downregulated.Among the altered microRNAs were miR-9/9*,miR-29b,miR-124a,miR-132,miR-128,miR-139,miR-122,miR-138,miR-23b,miR-135b,miR-181(all downregulated)and miR-448(upregulated),and similar changes had been previously found in Huntington’s disease patients.In the animal cell studies,the altered microRNAs included miR-9,miR-9*,miR-135b,miR-222(all downregulated)and miR-214(upregulated).In the animal models,overexpression of miR-155 and miR-196a caused a decrease in mutant huntingtin mRNA and protein level,lowered the mutant huntingtin aggregates in striatum and cortex,and improved performance in behavioral tests.Improved performance in behavioral tests also occurred with overexpression of miR-132 and miR-124.In the animal cell models,overexpression of miR-22 increased the viability of rat primary cortical and striatal neurons infected with mutant huntingtin and decreased huntingtin-enriched foci of≥2μm.Also,overexpression of miR-22 enhanced the survival of rat primary striatal neurons treated with 3-nitropropionic acid.Exogenous expression of miR-214,miR-146a,miR-150,and miR-125b decreased endogenous expression of huntingtin mRNA and protein in HdhQ111/HdhQ111 cells.Further studies with animal models of Huntington’s disease are warranted to validate these findings and identify specific microRNAs whose overexpression inhibits the production of mutant huntingtin protein and other harmful processes and may provide a more effective means of treating Huntington’s disease in patients and slowing its progression.

Adenyl cyclase activator forskolin protects against Huntington's disease-like neurodegenerative disorders

Long term suppression of succinate dehydrogenase by selective inhibitor 3-nitropropionic acid has been used in rodents to model Huntington＇s disease where mitochondrial dysfunction and oxidative damages are primary pathological hallmarks for neuronal damage. Improvements in learning and memory abilities, recovery of energy levels, and reduction of excitotoxicity damage can be achieved through activation of Adenyl cyclase enzyme by a specific phytochemical forskolin. In this study, intraperitoneal administration of 10 mg/kg 3-nitropropionic acid for 15 days in rats notably reduced body weight, worsened motor cocordination（grip strength, beam crossing task, locomotor activity）, resulted in learning and memory deficits, greatly increased acetylcholinesterase, lactate dehydrogenase, nitrite, and malondialdehyde levels, obviously decreased adenosine triphosphate, succinate dehydrogenase, superoxide dismutase, catalase, and reduced glutathione levels in the striatum, cortex and hippocampus. Intragastric administration of forskolin at 10, 20, 30 mg/kg dose-dependently reversed these behavioral, biochemical and pathological changes caused by 3-nitropropionic acid. These results suggest that forskolin exhibits neuroprotective effects on 3-nitropropionic acid-induced Huntington＇s disease-like neurodegeneration.

Factors contributing to clinical picture and progression of Huntington's disease

Huntington’s disease（HD）is an autosomal dominant,monogenic,progressive,neurodegenerative and rare disease with a frequency of10 per 100,000 in the Caucasian population and occurring more rarely in other races（Squitieri et al.,1994）.HD is,nevertheless,one of the most frequently and extensively studied diseases of those caused by a dynamic mutation.The HD mutation is located on the short arm of the 4th chromosome within the HTT gene.

Examination of Huntington's disease in a Chinese family

We report brain imaging and genetic diagnosis in a family from Wuhan, China, with a history of Huntington＇s disease. Among 17 family members across three generations, four patients （Ⅱ2, Ⅱ6, Ⅲ5, and Ⅲ9） show typical Huntington＇s disease, involuntary dance-like movements. Magnetic resonance imaging found lateral ventricular atrophy in three members （Ⅱ2, Ⅱ6, and Ⅲ5）. Moreover, genetic analysis identified abnormally amplified CAG sequence repeats （〉 40） in two members （Ⅲ5 and Ⅲ9）. Among borderline cases, with clinical symptoms and brain imaging features of Huntington＇s disease, two cases were identified （Ⅱ2 and Ⅱ6）, but shown by mutation analysis for CAG expansions in the important transcript 15 gene, to be non-Huntington＇s disease. Our findings suggest that clinical diagnosis of Huntington＇s disease requires a combination of clinical symptoms, radiological changes, and genetic diagnosis.

Emotion recognition and inhibitory control in manifest and pre-manifest Huntington’s disease: evidence from a new Stroop task

Huntington’s disease(HD)is a genetic neurodegenerative disorder that affects not only the motor but also the cognitive domain.In particular,cognitive symptoms such as impaired executive skills and deficits in recognizing other individuals’mental state may emerge many years before the motor symptoms.This study was aimed at testing two cognitive hypotheses suggested by previous research with a new Stroop task created for the purpose:1)the impairment of emotion recognition in HD is moderated by the emotions’valence,and 2)inhibitory control is impaired in HD.Forty manifest and 20 pre-manifest HD patients and their age-and gender-matched controls completed both the traditional“Stroop Color and Word Test”(SCWT)and the newly created“Stroop Emotion Recognition under Word Interference Task”(SERWIT),which consist in 120 photographs of sad,calm,or happy faces with either congruent or incongruent word interference.On the SERWIT,impaired emotion recognition in manifest HD was moderated by emotion type,with deficits being larger in recognizing sadness and calmness than in recognizing happiness,but it was not moderated by stimulus congruency.On the SCWT,six different interference scores yielded as many different patterns of group effects.Overall our results corroborate the hypothesis that impaired emotion recognition in HD is moderated by the emotions’valence,but do not provide evidence for the hypothesis that inhibitory control is impaired in HD.Further research is needed to learn more about the psychological mechanisms underlying the moderating effect of emotional valence on impaired emotion recognition in HD,and to corroborate the hypothesis that the inhibitory processes involved in Stroop tasks are not impaired in HD.Looking beyond this study,the SERWIT promises to make important contributions to disentangling the cognitive and the psychomotor aspects of neurological disorders.The research was approved by the Ethics Committee of the“Istituto Leonarda Vaccari”,Rome on January 24,2018.

Hope in Huntington's disease A survey in counseling patients with Huntington's disease,as well as the caregivers

BACKGROUND： It is difficult to attract interest in non-compulsory, preventive, medical care, and persons diagnosed with certain diseases often ignore the existence of these diseases. However, Huntington＇s disease （HD） is an exception. OBJECTIVE： To qualitatively analyze factors motivating HD patients to participate in a study, namely the European Huntington＇s Disease Network （EHDN） REGISTRY. DESIGN, TIME AND SETTING： An observational survey was conducted in the EHDN Study Site in Poznan, Poland between 2007 and 2008. PARTICIPANTS： The study involved 22 persons affected with HD and 3 pre-symptomatic individuals totaling 9 males and 16 females. The 24 participants in this study had 24 different caregivers. A total of 25 symptomatic or pre-symptomatic subjects participated in the initial REGISTRY visit, as well as 6 in the second, and 1 in the third. All subjects did not know each other prior to the visit. METHODS： A mutation in the IT15 gene was confirmed in each patient or pre-symptomatic mutation carrier. An in-depth interview produced detailed information on the HD patients, as well as the caregivers, for the REGISTRY study. MAIN OUTCOME MEASURES： A qualitative analysis of the factors motivating HD patients and the pre-symptomatic mutation carriers to participate in the REGISTRY longitudinal, observational, research project was performed. RESULTS： The primary motivating factor for involvement of HD patients and the caregivers in the REGISTRY study was the hope that an effective HD therapy would soon be discovered. In HD patients and the pre-symptomatic group, the response to participate in the REGISTRY project reached 100%, despite the fact that they knew the project was only an observational study. CONCLUSION： Patient hope is thought to be a factor for engaging in preventive, therapeutic activities. However, this is rarely mentioned in medical papers and clinical textbooks, and is usually overlooked in medical teaching. Clearly, efforts should be made to include this in clinical practice.

High resolution impedance manometric findings in dysphagia of Huntington's disease

Conventional manometry presents significant challenges,especially in assessment of pharyngeal swallowing,because of the asymmetry and deglutitive movements of oropharyngeal structures.It only provides information about intraluminal pressure and thus it is difficult to study functional details of esophageal motility disorders.New technology of solid high resolution impedance manometry(HRIM),with 32 pressure sensors and 6 impedance sensors,is likely to provide better assessment of pharyngeal swallowing as well as more information about esophageal motility disorders.However,the clinical usefulness of application of HRIM in patients with oropharyngeal dysphagia or esophageal dysphagia is not known.We experienced a case of Huntington's disease presenting with both oropharyngeal and esophageal dysphagia,in which HRIM revealed the mechanism of oropharyngeal dysphagia and provided comprehensive information about esophageal dysphagia.

Mitochondria in Huntington’s disease:implications in pathogenesis and mitochondrial-targeted therapeutic strategies

Huntington’s disease is a genetic disease caused by expanded CAG repeats on exon 1 of the huntingtin gene located on chromosome 4.Compelling evidence implicates impaired mitochondrial energetics,altered mitochondrial biogenesis and quality control,disturbed mitochondrial trafficking,oxidative stress and mitochondrial calcium dyshomeostasis in the pathogenesis of the disorder.Unfortunately,conventional mitochondrial-targeted molecules,such as cysteamine,creatine,coenzyme Q10,or triheptanoin,yielded negative or inconclusive results.However,future therapeutic strategies,aiming to restore mitochondrial biogenesis,improving the fission/fusion balance,and improving mitochondrial trafficking,could prove useful tools in improving the phenotype of Huntington’s disease and,used in combination with genome-editing methods,could lead to a cure for the disease.

Glyco-sphingo biology: a novel perspective for potential new treatments in Huntington's disease

Huntington＇s disease （HD） is the most common dominantly inherited neurodegenerative disorder, mainly characterized by the progressive striatal and cortical neurodegeneration and as- sociated motor, cognitive and behavioural disturbances （Zuccato et al., 2010）. The disease-causing mutation is an expansion of a GAG trinucleotide repeat （〉 36 repeats） encoding a polygluta- mine stretch in the N-terminal region ofhuntingtin （Htt） （Zuc- cato et al., 2010）, a ubiquitous protein whose function is still unclear （Zuccato et al., 2010）. Expansion of the polyQ stretch endows mutant Htt （mHtt） with toxic properties, and results in the development of a broad array of undesirable effects in both neuronal and non-neuronal cells （Zuccato et al., 2010）. Among all cellular dysfunctions and biochemical imbalances classically associated with HD, perturbed metabolism of （glyco） sphingolipids appears to play a crucial role in the pathogenesis of the disease. Over the last years, we and other have extensively contributed to these findings （Desplats et al., 2007;

Histone methylation in Huntington's disease:are bivalent promoters the critical targets?

Huntington’s disease（HD）is a currently incurable,late onset,progressive,ultimately fatal neurological disorder（Bates et al.,2015）.We have recently published the results of comprehensive genetic interaction tests aimed at identification of histone methyltransferases and demethylases involved in HD pathogenesis in a Drosophila model of the disease（Song et al.,2018）.

“With This Disease, You Take Whatever Chances There Are”—A Study on Socio-Cultural and Psychological Aspects of Experiments Regarding Huntington’s Disease

Although relatively rare, Huntington’s disease (HD) has fatal consequences. There is no cure for the disease, which leads to an early death. Worldwide, scientists are trying to develop therapeutic methods that could cure the disease, including new molecular gene therapeutic methods. At Lund University, research on HD is now about to step from animal models to trials with humans. The project is special in its design since it involves both medical studies and socio-cultural and psychological research to explore and meet the many challenges that experimental trials with HD patients give rise to. The aim of the present study was to investigate the viewpoints of individuals affected by HD on the issues of participation and exerting influence if taking part in a medical study on gene therapy that has not previously been tested on humans. A total of 16 participants, recruited through the national association for HD and through the neurological clinic at Lund University in Sweden, took part in a focus group or in a survey study. A thematic analysis, to explore the transcribed text from the focus groups as well as from the written mail responses, was conducted by means of Nvivo, a program for qualitative data analysis. Results showed three main themes expressing reasons for participation: participation as a last resort, as an activity of hope, and as a way to take responsibility for the development of a cure that will benefit future generations. The responses relating to the question about affected individuals’ view of exerting influence resulted in two themes. The first theme was having a voice when researchers design experiments, which may give a sense of receiving respect. The second was that influence is an essential part of the information process before agreeing to take part in an experimental trail.

The Effect of Music Therapy for Patients With Huntington＇s Disease： A Systematic Literature Review

Huntington＇s disease is a progressive, neurodegenerative, and autosomal dominant disease characterized by motor- and psychiatric disturbances, and cognitive decline. Since there is no cure, all treatment is aimed at improving quality of life. One form of non-drug therapy which is barely recognized, is music therapy. The literature on its use and effect in patients with Huntington＇s disease is limited. We therefore performed a detailed literature survey in order to delineate the different types of music therapy interventions and their aims. Music therapy studies were included when targeting： （1） motor disturbances; （2） cognitive disturbances; （3） psychiatric disturbances; and （4） emotional/social disturbances. A total of eight studies that met these criteria were analyzed. We found that music therapy interventions vary throughout the different stages of the disease and are not yet applied optimally. Not the stage of the disease but the individual treatment goals seem to be more determinative for the music therapy indications. In conclusion, precise aims and methods in relation to the stage of the disease are not well determined. There is a need for systematic study of this treatment option.

Analysis of the Epigenetic Mechanism and Treatment of Huntington’s Disease

Huntington’s disease(HD)is an irreversible neurodegenerative disorder that is inherited in an autosomal dominant manner.In HD,many regions of the human brain are affected,including the striatum,thalamus,and cortex.The mechanism is by the expansion of CAG repeats,which encode glutamine(Q)in the Huntingtin gene on chromosome 4p16.3.Patients with more CAG repeats tend to have a younger age of onset and a higher risk.Mutant HTT protein,translated from mtHtt,would congregate or interact with other proteins,causing damage to the human body.Patients with HD show symptoms like chorea,which is an involuntary motor disability,cognitive deterioration,and psychiatric disturbances.Except for the genetic pathology of HD,the epigenetic mechanism of this disease has made a lot of progress in recent years.This paper primarily focuses on the alternation of deoxyribonucleic acid(DNA)methylation,histone modification,and non-coding ribonucleic acids(ncRNAs)in HD as well as the advancements of epigenetic therapy and healthcare in HD.

Episodic Learning and Memory in Prodromal Huntington’s Disease: The Role of Multimodal Encoding and Selective Reminding

This study investigated episodic memory in prodromal HD. Three groups were compared (N = 70): mutation carriers with less than 12.5 years to disease onset (n = 16), mutation carriers with 12.5 or more years to disease onset (n = 16), and noncarriers (n = 38). Episodic memory was assessed using the Fuld Object Memory Evaluation, which included multimodal presentation and selective reminding, and the Claeson-Dahl Learning Test which included verbal repeated presentation and recall trials. Both carrier groups demonstrated deficient episodic memory compared to noncarriers. The results suggest deficient episodic memory in prodromal HD, and that inconsistent retrieval contributes to these deficits. Multimodal presentation attenuates the deficits.

Induced pluripotent stem cells from Huntington's disease patients:a promising approach to define and correct disease-related alterations

Adult somatic cells such as skin or blood cells from either health donors or patients can be reprogrammed into induced pluripotent stem cells(iPSCs).Given their unlimited self-renewal and differentiation capacities,iPSCs are an invaluable resource to generate terminally differentiated cells.Thus,iPSCs can facilitate the study of human diseases and drug screening,holding great promise for regenerative medicine.Another significant advantage of iPSC disease-modeling is that normal and mutant proteins are expressed at endogenous levels.In addition,subtle phenotypes and the effects of genetic background variations can be assessed by comparison between iPSC lines obtained from different patients and healthy donors as well as isogenic lines,in which disease-related mutations are corrected.