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Cold Spring Harbor Perspectives in... Jul 2017Huntington's disease is a late-onset neurodegenerative disease caused by a CAG trinucleotide repeat in the gene encoding the huntingtin protein. Despite its well-defined... (Review)
Review
Huntington's disease is a late-onset neurodegenerative disease caused by a CAG trinucleotide repeat in the gene encoding the huntingtin protein. Despite its well-defined genetic origin, the molecular and cellular mechanisms underlying the disease are unclear and complex. Here, we review some of the currently known functions of the wild-type huntingtin protein and discuss the deleterious effects that arise from the expansion of the CAG repeats, which are translated into an abnormally long polyglutamine tract. Finally, we outline some of the therapeutic strategies that are currently being pursued to slow down the disease.
Topics: Gene Expression Regulation; Humans; Huntingtin Protein; Huntington Disease; Nerve Tissue Proteins; Nuclear Proteins; Trinucleotide Repeats
PubMed: 27940602
DOI: 10.1101/cshperspect.a024240 -
International Journal of Molecular... Aug 2021Huntington's disease (HD) is a neurodegenerative disorder caused by a CAG expansion in the HD gene. The disease is characterized by neurodegeneration, particularly in... (Review)
Review
Huntington's disease (HD) is a neurodegenerative disorder caused by a CAG expansion in the HD gene. The disease is characterized by neurodegeneration, particularly in the striatum and cortex. The first symptoms usually appear in mid-life and include cognitive deficits and motor disturbances that progress over time. Despite being a genetic disorder with a known cause, several mechanisms are thought to contribute to neurodegeneration in HD, and numerous pre-clinical and clinical studies have been conducted and are currently underway to test the efficacy of therapeutic approaches targeting some of these mechanisms with varying degrees of success. Although current clinical trials may lead to the identification or refinement of treatments that are likely to improve the quality of life of those living with HD, major efforts continue to be invested at the pre-clinical level, with numerous studies testing novel approaches that show promise as disease-modifying strategies. This review offers a detailed overview of the currently approved treatment options for HD and the clinical trials for this neurodegenerative disorder that are underway and concludes by discussing potential disease-modifying treatments that have shown promise in pre-clinical studies, including increasing neurotropic support, modulating autophagy, epigenetic and genetic manipulations, and the use of nanocarriers and stem cells.
Topics: Animals; Autophagy; Clinical Trials as Topic; Disease Management; Disease Models, Animal; Humans; Huntington Disease
PubMed: 34445070
DOI: 10.3390/ijms22168363 -
Neuron Mar 2016Huntingtin (HTT) is now a famous protein because an abnormal expansion of a glutamine stretch (polyQ) in its N-terminal sequence leads to the devastating... (Review)
Review
Huntingtin (HTT) is now a famous protein because an abnormal expansion of a glutamine stretch (polyQ) in its N-terminal sequence leads to the devastating neurodegenerative disorder Huntington's disease (HD). The gene encoding huntingtin, HTT, and its dominantly inherited mutation were identified more than 20 years ago. Subsequently, in the hope of finding a cure for HD, there has been intense research aimed at understanding the molecular mechanisms underlying the deleterious effects of the presence of the abnormal polyQ expansion in HTT. Notwithstanding with the value of this approach, evidence has been emerging of a potential role of context and function of the HTT protein in the specificity and severity of the pathogenicity. HTT is ubiquitous both at the tissue and subcellular levels. It interacts with many partners and has long been considered having no clearly defined cellular function. Based on research over the past 20 years, specifically focused on the function of wild-type HTT, we reconsider the literature describing HTT-regulated molecular and cellular mechanisms that could be dysfunctional in HD and their possible physiological consequences for patients.
Topics: Animals; Biology; Humans; Huntingtin Protein; Huntington Disease; Mutation; Nerve Tissue Proteins
PubMed: 26938440
DOI: 10.1016/j.neuron.2016.02.003 -
Nature Reviews. Neurology Apr 2014Huntington disease (HD) can be seen as a model neurodegenerative disorder, in that it is caused by a single genetic mutation and is amenable to predictive genetic... (Review)
Review
Huntington disease (HD) can be seen as a model neurodegenerative disorder, in that it is caused by a single genetic mutation and is amenable to predictive genetic testing, with estimation of years to predicted onset, enabling the entire range of disease natural history to be studied. Structural neuroimaging biomarkers show that progressive regional brain atrophy begins many years before the emergence of diagnosable signs and symptoms of HD, and continues steadily during the symptomatic or 'manifest' period. The continued development of functional, neurochemical and other biomarkers raises hopes that these biomarkers might be useful for future trials of disease-modifying therapeutics to delay the onset and slow the progression of HD. Such advances could herald a new era of personalized preventive therapeutics. We describe the natural history of HD, including the timing of emergence of motor, cognitive and emotional impairments, and the techniques that are used to assess these features. Building on this information, we review recent progress in the development of biomarkers for HD, and potential future roles of these biomarkers in clinical trials.
Topics: Biomarkers; Brain; Humans; Huntington Disease; Magnetic Resonance Imaging; Neuroimaging; Radionuclide Imaging
PubMed: 24614516
DOI: 10.1038/nrneurol.2014.24 -
Ageing Research Reviews Sep 2021Huntington's disease (HD) is an autosomal neurodegenerative disorder caused by extended trinucleotide CAG repetition in the HTT gene. Wild-type huntingtin protein (HTT)... (Review)
Review
Huntington's disease (HD) is an autosomal neurodegenerative disorder caused by extended trinucleotide CAG repetition in the HTT gene. Wild-type huntingtin protein (HTT) is essential, involved in a variety of crucial cellular functions such as vesicle transportation, cell division, transcription regulation, autophagy, and tissue maintenance. The mutant HTT (mHTT) proteins in the body interfere with HTT's normal cellular functions and cause additional detrimental effects. In this review, we discuss multiple approaches targeting DNA and RNA to reduce mHTT expression. These approaches are categorized into non-allele-specific silencing and allele-specific-silencing using Single Nucleotide Polymorphisms (SNPs) and haplogroup analysis. Additionally, this review discusses a potential application of recent CRISPR prime editing technology in targeting HD.
Topics: Alleles; Gene Expression Regulation; Gene Targeting; Humans; Huntingtin Protein; Huntington Disease
PubMed: 34098113
DOI: 10.1016/j.arr.2021.101385 -
Molecular Neurobiology Mar 2023The pathogenic mechanisms of these diseases must be well understood for the treatment of neurological disorders such as Huntington's disease. Huntington's Disease (HD),... (Review)
Review
The pathogenic mechanisms of these diseases must be well understood for the treatment of neurological disorders such as Huntington's disease. Huntington's Disease (HD), a dominant and neurodegenerative disease, is characterized by the CAG re-expansion that occurs in the gene encoding the polyglutamine-expanded mutant Huntingtin (mHTT) protein. Genome editing approaches include zinc-finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs) and Clustered Regularly Interspaced Short Palindromic Repeats/Caspase 9 (CRISPR/Cas9) systems. CRISPR/Cas9 technology allows effective gene editing in different cell types and organisms. Through these systems are created isogenic control of human origin induced pluripotent stem cells (iPSCs). In human and mouse models, HD-iPSC lines can be continuously corrected using these systems. HD-iPSCs can be corrected through the CRISPR/Cas9 system and the cut-and-paste mechanism using isogenic control iPSCs. This mechanism is a piggyBac transposon-based selection system that can effectively switch between vectors and chromosomes. In studies conducted, it has been determined that in neural cells derived from HD-iPSC, there are isogenic controls as corrected lines recovered from phenotypic abnormalities and gene expression changes. It has been determined that trinucleotide repeat disorders occurring in HD can be cured by single-guide RNA (sgRNA) and normal exogenous DNA restoration, known as the single guideline RNA specific to Cas9. The purpose of this review in addition to give general information about HD, a neurodegenerative disorder is to explained the role of CRISPR/Cas9 system with iPSCs in HD treatment.
Topics: Mice; Animals; Humans; CRISPR-Cas Systems; Huntington Disease; Neurodegenerative Diseases; Gene Editing; Neurons
PubMed: 36482283
DOI: 10.1007/s12035-022-03150-5 -
Journal of Genetics Jul 2018Huntington's disease (HD) is caused due to an abnormal expansion of polyglutamine repeats in the first exon of huntingtin gene. The mutation in huntingtin causes... (Review)
Review
Huntington's disease (HD) is caused due to an abnormal expansion of polyglutamine repeats in the first exon of huntingtin gene. The mutation in huntingtin causes abnormalities in the functioning of protein, leading to deleterious effects ultimately to the demise of specific neuronal cells.The disease is inherited in an autosomal dominant manner and leads to a plethora of neuropsychiatric behaviour and neuronal cell death mainly in striatal and cortical regions of the brain, eventually leading to death of the individual. The discovery of the mutant gene led to a surge in molecular diagnostics of the disease and in making different transgenic models in different organisms to understand the function of wild-type and mutant proteins. Despite difficult challenges, there has been a significant increase in understanding the functioning of the protein in normal and other gain-of-function interactions in mutant form. However, there have been no significant improvements in treatments of the patients suffering from this ailment and most of the treatment is still symptomatic. HD warrants more attention towards better understanding and treatment as more advancement in molecular diagnostics and therapeutic interventions are available. Several different transgenic models are available in different organisms, ranging from fruit flies to primate monkeys, for studies on understanding the pathogenicity of the mutant gene. It is the right time to assess the advancement in the field and try new strategies for neuroprotection using key pathways as target. The present review highlights the key ingredients of pathology in the HD and discusses important studies for drug trials and future goals for therapeutic interventions.
Topics: Animals; Humans; Huntington Disease; Mutation; Neuroprotection; Prevalence
PubMed: 30027901
DOI: No ID Found -
Neuron Mar 2019Huntington's disease is caused by an abnormally expanded CAG repeat expansion in the HTT gene, which confers a predominant toxic gain of function in the mutant... (Review)
Review
Huntington's disease is caused by an abnormally expanded CAG repeat expansion in the HTT gene, which confers a predominant toxic gain of function in the mutant huntingtin (mHTT) protein. There are currently no disease-modifying therapies available, but approaches that target proximally in disease pathogenesis hold great promise. These include DNA-targeting techniques such as zinc-finger proteins, transcription activator-like effector nucleases, and CRISPR/Cas9; post-transcriptional huntingtin-lowering approaches such as RNAi, antisense oligonucleotides, and small-molecule splicing modulators; and novel methods to clear the mHTT protein, such as proteolysis-targeting chimeras. Improvements in the delivery and distribution of such agents as well as the development of objective biomarkers of disease and of HTT lowering pharmacodynamic outcomes have brought these potential therapies to the forefront of Huntington's disease research, with clinical trials in patients already underway.
Topics: Animals; CRISPR-Cas Systems; Genetic Therapy; Humans; Huntingtin Protein; Huntington Disease
PubMed: 30844400
DOI: 10.1016/j.neuron.2019.01.039 -
CNS Neuroscience & Therapeutics Apr 2018
Topics: Animals; Humans; Huntington Disease
PubMed: 29582586
DOI: 10.1111/cns.12841 -
Journal of Huntington's Disease 2017A number of studies evaluating physical therapy and exercise interventions in Huntington's disease have been conducted over the past 15 years. However, an assessment of... (Review)
Review
BACKGROUND
A number of studies evaluating physical therapy and exercise interventions in Huntington's disease have been conducted over the past 15 years. However, an assessment of the quality and strength of the evidence in support of these interventions is lacking.
OBJECTIVE
The purpose of this systematic review was to investigate the effectiveness of physical therapy and exercise interventions in people with Huntington's disease, and to examine the perceptions of patients, families and caregivers of these interventions.
METHODS
This mixed-methods systematic review utilized the Joanna Briggs Institute (JBI) approach and extraction tools to evaluate the literature from January 2003 until May 2016. The review considered interventions that included exercise and physical therapy interventions, and included both quantitative and qualitative outcome measures.
RESULTS
Twenty (20) studies met the inclusion criteria, including eighteen (18) that had quantitative outcome measures and two (2) that utilized qualitative methods. JBI Levels of evidence for the 18 quantitative studies were as follows: Eight studies were at evidence Level 1, seven were at Level 2, two were at Level 3, and one was at Level 4.
CONCLUSIONS
Our review suggests that there is preliminary support for the benefits of exercise and physical activity in Huntington's disease in terms of motor function, gait speed, and balance, as well as a range of physical and social benefits identified through patient-reported outcomes. Variability in mode of intervention as well as outcome measures limits the interpretability of these studies, and high-quality studies that incorporate adaptive trial designs for this rare disease are needed.
Topics: Exercise Therapy; Female; Humans; Huntington Disease; Male; Outcome Assessment, Health Care; Physical Therapy Modalities
PubMed: 28968244
DOI: 10.3233/JHD-170260