Dietary fasting and time-restricted eating in Huntington's disease: therapeutic potential and underlying mechanisms.

Huntington's disease (HD) is a devastating neurodegenerative disorder caused by aggregation of the mutant huntingtin (mHTT) protein, resulting from a CAG repeat expansion in the huntingtin gene HTT. HD is characterized by a variety of debilitating symptoms including involuntary movements, cognitive impairment, and psychiatric disturbances. Despite considerable efforts, effective disease-modifying treatments for HD remain elusive, necessitating exploration of novel therapeutic approaches, including lifestyle modifications that could delay symptom onset and disease progression. Recent studies suggest that time-restricted eating (TRE), a form of intermittent fasting involving daily caloric intake within a limited time window, may hold promise in the treatment of neurodegenerative diseases, including HD. TRE has been shown to improve mitochondrial function, upregulate autophagy, reduce oxidative stress, regulate the sleep-wake cycle, and enhance cognitive function. In this review, we explore the potential therapeutic role of TRE in HD, focusing on its underlying physiological mechanisms. We discuss how TRE might enhance the clearance of mHTT, recover striatal brain-derived neurotrophic factor levels, improve mitochondrial function and stress-response pathways, and synchronize circadian rhythm activity. Understanding these mechanisms is critical for the development of targeted lifestyle interventions to mitigate HD pathology and improve patient outcomes. While the potential benefits of TRE in HD animal models are encouraging, future comprehensive clinical trials will be necessary to evaluate its safety, feasibility, and efficacy in persons with HD.

Huntington's Disease: Complex Pathogenesis and Therapeutic Strategies.

Huntington's disease (HD) arises from the abnormal expansion of CAG repeats in the huntingtin gene (HTT), resulting in the production of the mutant huntingtin protein (mHTT) with a polyglutamine stretch in its N-terminus. The pathogenic mechanisms underlying HD are complex and not yet fully elucidated. However, mHTT forms aggregates and accumulates abnormally in neuronal nuclei and processes, leading to disruptions in multiple cellular functions. Although there is currently no effective curative treatment for HD, significant progress has been made in developing various therapeutic strategies to treat HD. In addition to drugs targeting the neuronal toxicity of mHTT, gene therapy approaches that aim to reduce the expression of the mutant HTT gene hold great promise for effective HD therapy. This review provides an overview of current HD treatments, discusses different therapeutic strategies, and aims to facilitate future therapeutic advancements in the field.

Health state utility estimates for value assessments of novel treatments in Huntington's disease: a systematic literature review.

BACKGROUND: Huntington's disease (HD) is a progressive neurodegenerative disease with a devastating impact on patients and their families. Quantifying how treatments affect patient outcomes is critical for informing reimbursement decisions. Many countries mandate a formal value assessment in which the treatment benefit is measured as quality-adjusted life-years, calculated with the use of utility estimates that reflect respondents' preferences for health states. OBJECTIVE: To summarize published health state utility data in HD and identify gaps and uncertainties in the data available that could be used to inform value assessments. METHODS: We conducted a systematic literature review of studies that used preference-based instruments (e.g., EQ-5D and SF-6D) to estimate utility values for people with HD. The studies were published between January 2012 and December 2022. RESULTS: Of 383 articles screened, 16 articles reported utility values estimated in 11 distinct studies. The utility measure most frequently reported was EQ-5D (9/11 studies). Two studies reported SF-6D data; one used time trade-off methods to value health state descriptions (vignettes). Although utility scores generally worsened to a lower value with increased HD severity, the estimates varied considerably across studies. The EQ-5D index range was 0.89 - 0.72 for mild/prodromal HD and 0.71 - 0.37 for severe/late-stage disease. CONCLUSIONS: This study uncovered high variability in published utility estimates, indicating substantial uncertainty in existing data. Further research is needed to better understand preferences and valuation across all stages and domains of HD symptoms and the degree to which generic utility measures capture the impact of cognitive changes on quality of life.

Huntington's Disease Clinical Trials Corner: March 2024.

In this edition of the Huntington's Disease Clinical Trials Update, we expand on the ongoing program from VICO Therapeutics and on the recently terminated VIBRANT-HD clinical trials. We also discuss updates from uniQure's AMT-130 program and PTC therapeutics' trial of PTC518 and list all currently registered and ongoing clinical trials in Huntington's disease.

Large animal models for Huntington's disease research.

Huntington's disease (HD) is a hereditary neurodegenerative disorder for which there is currently no effective treatment available. Consequently, the development of appropriate disease models is critical to thoroughly investigate disease progression. The genetic basis of HD involves the abnormal expansion of CAG repeats in the huntingtin ( HTT) gene, leading to the expansion of a polyglutamine repeat in the HTT protein. Mutant HTT carrying the expanded polyglutamine repeat undergoes misfolding and forms aggregates in the brain, which precipitate selective neuronal loss in specific brain regions. Animal models play an important role in elucidating the pathogenesis of neurodegenerative disorders such as HD and in identifying potential therapeutic targets. Due to the marked species differences between rodents and larger animals, substantial efforts have been directed toward establishing large animal models for HD research. These models are pivotal for advancing the discovery of novel therapeutic targets, enhancing effective drug delivery methods, and improving treatment outcomes. We have explored the advantages of utilizing large animal models, particularly pigs, in previous reviews. Since then, however, significant progress has been made in developing more sophisticated animal models that faithfully replicate the typical pathology of HD. In the current review, we provide a comprehensive overview of large animal models of HD, incorporating recent findings regarding the establishment of HD knock-in (KI) pigs and their genetic therapy. We also explore the utilization of large animal models in HD research, with a focus on sheep, non-human primates (NHPs), and pigs. Our objective is to provide valuable insights into the application of these large animal models for the investigation and treatment of neurodegenerative disorders.

The Huntington's Disease Gene Discovery.

The gene for Huntington's disease (HD) was discovered in 1993, after an international collaborative initiative that led researchers to remote regions of South America. It was the most remarkable milestone, since George Huntington's initial description. Through the phenomenological discussions led by Jean-Martin Charcot and Willian Osler, and finally Americo Negrette's reports, which served as the inspiration for the Venezuela Project led by Nancy Wexler, the journey toward discovering the Huntington's disease (HD) gene was marked by substantial efforts. This monumental achievement involved the analysis of more than 18,000 blood samples and gathered dozens of researchers in an integrated effort, enabling the mapping of the gene on chromosome 4 in 1983 and leading, a decade later, to the precise localization and identification of the HTT gene. The discovery of the HD mutation represented a pivotal moment in the field of genetics and neurology, significantly enhancing our understanding of the disease and creating opportunities for future treatments. The progress made and the knowledge gained during this journey catalyzed the development of many innovative molecular techniques that have advanced research in other medical conditions. In this article, the authors celebrate three decades of this memorable event, revisiting the historical aspects, providing insights into the techniques developed, and delving into the paths that ultimately led to the discovery of the HD gene. © 2024 International Parkinson and Movement Disorder Society.

Perceptions of palliative care in Huntington's disease: A qualitative study.

INTRODUCTION: Palliative care focuses on improving patient and family quality of life by managing symptoms, psychosocial issues and spiritual concerns. Huntington's disease is a progressive neurodegenerative disorder with no current disease modifying therapy. Although the palliative care model has been postulated to be an integral part of HD care, there are gaps in knowledge about how this care should be implemented. This study aims to identify perceptions of palliative care in Huntington's Disease (HD), palliative care needs of people living with HD, and at what point they feel they would benefit from these resources. METHODS: Participants volunteered from a large academic institution patient base to be involved in semi structured interviews that explored patient and caregiver experience surrounding their diagnosis, disease management, quality of life, and areas for improvement. Inclusion criteria for participants was a diagnosis of Huntington's disease and/or a self-identified caregiver of a person living with the disease. RESULTS: A total of 12 independent patients, three independent caregivers, and five dyads completed the interviews. Themes identified included needs that would provide patient and caregiver centered treatment, current gaps in care, an openness and desire for palliative care, and knowledge about the desired timing of palliative care in treatment plans. CONCLUSION: People living with HD and caregivers of people with HD most desire access to treatment that would focus on symptom management, availability of social resources, advanced care planning and spiritual wellbeing. The preferred timing of this intervention for most individuals would be at the onset of symptoms.

Perinatal Tissue-Derived Stem Cells: An Emerging Therapeutic Strategy for Challenging Neurodegenerative Diseases.

Over the past 20 years, stem cell therapy has been considered a promising option for treating numerous disorders, in particular, neurodegenerative disorders. Stem cells exert neuroprotective and neurodegenerative benefits through different mechanisms, such as the secretion of neurotrophic factors, cell replacement, the activation of endogenous stem cells, and decreased neuroinflammation. Several sources of stem cells have been proposed for transplantation and the restoration of damaged tissue. Over recent decades, intensive research has focused on gestational stem cells considered a novel resource for cell transplantation therapy. The present review provides an update on the recent preclinical/clinical applications of gestational stem cells for the treatment of protein-misfolding diseases including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS). However, further studies should be encouraged to translate this promising therapeutic approach into the clinical setting.

Facilitators and barriers in caring for a person with Huntington's disease: input for a remote support program.

OBJECTIVES: This study aims to provide more insight into possible barriers and facilitators caregivers of people with Huntington's disease (HD) encounter, and what their needs and wishes are regarding a remote support program. METHODS: In total, 27 persons participated in four focus group interviews. Eligible participants were caregivers (n = 19) of a person with HD, and healthcare professionals (n = 8) involved in HD care. Qualitative data were analyzed by two researchers who independently performed an inductive content analysis. RESULTS: Four major themes emerged from the data, including (1) a paradox between taking care of yourself and caring for others; (2) challenges HD caregivers face in daily life, including lack of HD awareness, taboo and shame, feelings of loneliness, concerns about heredity and children, and coping with HD symptoms; (3) facilitators in the caregiving process, including a social network, professional support, openness, talking in early phases, and daily structure; (4) needs regarding a support program. CONCLUSION: These insights will be used to develop a remote support program for HD caregivers, using a blended and self-management approach. Newly developed and tailored support should be aimed at empowering caregivers in their role and help them cope with their situation, taking into account barriers and facilitators.

Dietary fibre confers therapeutic effects in a preclinical model of Huntington's disease.

Huntington's disease (HD) is a neurodegenerative disorder involving psychiatric, cognitive and motor deficits, as well as peripheral symptoms, including gastrointestinal dysfunction. The R6/1 HD mouse model expresses a mutant human huntingtin transgene and has been shown to provide an accurate disease model. Recent evidence of gut microbiome disruption was shown in preclinical and clinical HD. Therefore, we aimed to assess the potential role of gut microbial modulation in the treatment of HD. The R6/1 HD mice and wild-type littermate controls were randomised to receive diets containing different amounts of fibre: high-fibre (10 % fibre), control (5 % fibre), or zero-fibre (0 % fibre), from 6 to 20 weeks of age. We characterized the onset and progression of motor, cognitive and affective deficits, as well as gastrointestinal function and gut morphological changes. Faeces were collected for gut microbiome profiling using 16S rRNA sequencing, at 14 and 20 weeks of age. When compared to the control diet, high-fibre diet improved the performance of HD mice in behavioral tests of cognitive and affective function, as well as the gastrointestinal function of both HD and wild-type mice. While the diets changed the beta diversity of wild-type mice, no statistical significance was observed at 14 or 20 weeks of age within the HD mice. Analysis of Composition of Microbiomes with Bias Correction (ANCOM-BC) models were performed to evaluate microbiota composition, which identified differences, including a decreased relative abundance of the phyla Actinobacteriota, Campylobacterota and Proteobacteria and an increased relative abundance of the families Bacteroidaceae, Oscillospiraceae and Ruminococcaceae in HD mice when compared to wild-type mice after receiving high-fibre diet. PICRUSt2 revealed that high-fibre diet also decreased potentially pathogenic functional pathways in HD. In conclusion, high-fibre intake was effective in enhancing gastrointestinal function, cognition and affective behaviors in HD mice. These findings indicate that dietary fibre interventions may have therapeutic potential in Huntington's disease to delay clinical onset, and have implications for related disorders exhibiting dysfunction of the gut-brain axis.

An Overview of Specialist Services for Huntington's Disease in the United Kingdom.

BACKGROUND: Huntington's disease (HD) is a rare inherited neurodegenerative disorder characterized by complex evolving needs that change as the condition progresses. There is limited understanding about the organization of HD clinical services and their resourcing in the United Kingdom (UK). OBJECTIVE: To understand the organization and resourcing of specialist HD services for people with HD (PwHD) in the UKMethods:This cross-sectional study collected quantitative data via on online survey, and qualitative data via telephone semi-structured interviews. Descriptive statistics were used to describe quantitative outcomes, and qualitative results were analyzed using content analysis. RESULTS: A total of 31 specialist services for HD were identified. Of the 27 services that completed the online survey, 23 had an active multidisciplinary team of healthcare professionals (HCPs) and were led primarily by a mental health trust (26%) or tertiary referral hospital (26%). Specialist services offered outpatient clinics (96%), outreach in the community (74%), telemedicine (70%), inpatient beds (26%) and satellite clinics (26%). Many services indicated that their capacity (ability to see patients as often as needed with current resources) was difficult, with some services reporting more difficulty at the early or later stages of HD. Key resourcing gaps were identified with access to facilities, HCPs and referral networks. CONCLUSIONS: This research highlights the variation in organization and capacity within individual HD services as well as current resourcing and gaps in access that influence this capacity. Further research should be done to understand the impact of service organization and current resourcing gaps in access on the quality of care provided for PwHD in the UK.

Transplanted human neural stem cells rescue phenotypes in zQ175 Huntington's disease mice and innervate the striatum.

Huntington's disease (HD), a genetic neurodegenerative disorder, primarily affects the striatum and cortex with progressive loss of medium-sized spiny neurons (MSNs) and pyramidal neurons, disrupting cortico-striatal circuitry. A promising regenerative therapeutic strategy of transplanting human neural stem cells (hNSCs) is challenged by the need for long-term functional integration. We previously described that, with short-term hNSC transplantation into the striatum of HD R6/2 mice, human cells differentiated into electrophysiologically active immature neurons, improving behavior and biochemical deficits. Here, we show that long-term (8 months) implantation of hNSCs into the striatum of HD zQ175 mice ameliorates behavioral deficits, increases brain-derived neurotrophic factor (BDNF) levels, and reduces mutant huntingtin (mHTT) accumulation. Patch clamp recordings, immunohistochemistry, single-nucleus RNA sequencing (RNA-seq), and electron microscopy demonstrate that hNSCs differentiate into diverse neuronal populations, including MSN- and interneuron-like cells, and form connections. Single-nucleus RNA-seq analysis also shows restoration of several mHTT-mediated transcriptional changes of endogenous striatal HD mouse cells. Remarkably, engrafted cells receive synaptic inputs, innervate host neurons, and improve membrane and synaptic properties. Overall, the findings support hNSC transplantation for further evaluation and clinical development for HD.

Limitations of Dual-Single Guide RNA CRISPR Strategies for the Treatment of Central Nervous System Genetic Disorders.

Huntington's disease (HD) is a fatal neurodegenerative disorder caused by a toxic gain-of-function CAG expansion in the first exon of the huntingtin (HTT) gene. The monogenic nature of HD makes mutant HTT (mHTT) inactivation a promising therapeutic strategy. Single nucleotide polymorphisms frequently associated with CAG expansion have been explored to selectively inactivate mHTT allele using the CRISPR/Cas9 system. One of such allele-selective approaches consists of excising a region flanking the first exon of mHTT by inducing simultaneous double-strand breaks at upstream and downstream positions of the mHTT exon 1. The removal of the first exon of mHTT deletes the CAG expansion and important transcription regulatory sites, leading to mHTT inactivation. However, the frequency of deletion events is yet to be quantified either in vitro or in vivo. Here, we developed accurate quantitative digital polymerase chain reaction-based assays to assess HTT exon 1 deletion in vitro and in fully humanized HU97/18 mice. Our results demonstrate that dual-single guide RNA (sgRNA) strategies are efficient and that 67% of HTT editing events are leading to exon 1 deletion in HEK293T cells. In contrast, these sgRNA actively cleaved HTT in HU97/18 mice, but most editing events do not lead to exon 1 deletion (10% exon 1 deletion). We also showed that the in vivo editing pattern is not affected by CAG expansion but may potentially be due to the presence of multiple copies of wildtype (wt)/mHTT genes HU97/18 mice as well as the slow kinetics of AAV-mediated CRISPR/Cas9 delivery.

Beyond Motor Deficits: Environmental Enrichment Mitigates Huntington's Disease Effects in YAC128 Mice.

Huntington's disease (HD) is a neurodegenerative genetic disorder characterized by motor, psychiatric, cognitive, and peripheral symptoms without effective therapy. Evidence suggests that lifestyle factors can modulate disease onset and progression, and environmental enrichment (EE) has emerged as a potential approach to mitigate the progression and severity of neurodegenerative processes. Wild-type (WT) and yeast artificial chromosome (YAC) 128 mice were exposed to different EE conditions. Animals from cohort 1 were exposed to EE between postnatal days 21 and 60, and animals from cohort 2 were exposed to EE between postnatal days 60 and 120. Motor and non-motor behavioral tests were employed to evaluate the effects of EE on HD progression. Monoamine levels, hippocampal cell proliferation, neuronal differentiation, and dendritic arborization were also assessed. Here we show that EE had an antidepressant-like effect and slowed the progression of motor deficits in HD mice. It also reduced monoamine levels, which correlated with better motor performance, particularly in the striatum. EE also modulated neuronal differentiation in the YAC128 hippocampus. These results confirm that EE can impact behavior, hippocampal neuroplasticity, and monoamine levels in YAC128 mice, suggesting this could be a therapeutic strategy to modulate neuroplasticity deficits in HD. However, further research is needed to fully understand EE's mechanisms and long-term effects as an adjuvant therapy for this debilitating condition.

From Pathogenesis to Therapeutics: A Review of 150 Years of Huntington's Disease Research.

Huntington's disease (HD) is a debilitating neurodegenerative genetic disorder caused by an expanded polyglutamine-coding (CAG) trinucleotide repeat in the huntingtin (HTT) gene. HD behaves as a highly penetrant dominant disorder likely acting through a toxic gain of function by the mutant huntingtin protein. Widespread cellular degeneration of the medium spiny neurons of the caudate nucleus and putamen are responsible for the onset of symptomology that encompasses motor, cognitive, and behavioural abnormalities. Over the past 150 years of HD research since George Huntington published his description, a plethora of pathogenic mechanisms have been proposed with key themes including excitotoxicity, dopaminergic imbalance, mitochondrial dysfunction, metabolic defects, disruption of proteostasis, transcriptional dysregulation, and neuroinflammation. Despite the identification and characterisation of the causative gene and mutation and significant advances in our understanding of the cellular pathology in recent years, a disease-modifying intervention has not yet been clinically approved. This review includes an overview of Huntington's disease, from its genetic aetiology to clinical presentation and its pathogenic manifestation. An updated view of molecular mechanisms and the latest therapeutic developments will also be discussed.

The translational potential of cholesterol-based therapies for neurological disease.

Cholesterol is an important metabolite and membrane component and is enriched in the brain owing to its role in neuronal maturation and function. In the adult brain, cholesterol is produced locally, predominantly by astrocytes. When cholesterol has been used, recycled and catabolized, the derivatives are excreted across the blood-brain barrier. Abnormalities in any of these steps can lead to neurological dysfunction. Here, we examine how precise interactions between cholesterol production and its use and catabolism in neurons ensures cholesterol homeostasis to support brain function. As an example of a neurological disease associated with cholesterol dyshomeostasis, we summarize evidence from animal models of Huntington disease (HD), which demonstrate a marked reduction in cholesterol biosynthesis with clinically relevant consequences for synaptic activity and cognition. In addition, we examine the relationship between cholesterol loss in the brain and cognitive decline in ageing. We then present emerging therapeutic strategies to restore cholesterol homeostasis, focusing on evidence from HD mouse models.

Advance Care Planning in Huntington Disease: The Elderly Care Physician's Perspective.

OBJECTIVE: Huntington disease (HD) has a poor prognosis. Decision-making capacity and communication ability may become impaired as the disease progresses. Therefore, HD patients are encouraged to engage in advance care planning (ACP). Elderly care physicians (ECPs) can play an important role in ACP in HD patients. However, little is known about their experiences in this role. The aim of this study is to gain insight into how ECPs practice ACP with HD patients. DESIGN: A qualitative interview study. SETTING AND PARTICIPANTS: Nine ECPs working in HD-specialized nursing homes in the Netherlands. METHODS: We conducted semistructured interviews with ECPs between June 2018 and July 2020. RESULTS: Two phases could be identified in the process of ACP. In the first phase, when the feared future seems to be far away, the ECP asks about the patient's wishes for the future in an accommodating manner. In the second phase, when the feared future is closer, future medical treatment and care becomes less hypothetical. Agreement has to be reached on upcoming treatment decisions. In this phase, the ECP takes a more guiding role, and consequently encounters more difficulties, such as maintaining a positive patient/family-physician relationship while dealing with disagreements with patient or family. Most participants shared their experiences with euthanasia when asked about ACP. When making a comparison of ACP between HD patients and patients with other neurodegenerative disorders in nursing homes, the ECPs emphasized the similarities. CONCLUSIONS AND IMPLICATIONS: ACP in HD can be classified into 2 phases, which differ in ECPs' approach and the complexity experienced by the ECP. Awareness of this finding may help to further develop training and education in ACP, including dealing with euthanasia, to make ECPs feel better equipped in practicing ACP in HD.