RNAi mechanisms in Huntington ’s disease therapy: siRNA versus shRNA

AbstractHuntington ’s Disease (HD) is a genetically dominant trinucleotide repeat disorder resulting from CAG repeats within the Huntingtin (HTT) gene exceeding a normal range (>  36 CAGs). Symptoms of the disease manifest in middle age and include chorea, dystonia, and cognitive decline. Typical latency from diagnosis to death is 20 years. There are currently no disease-modifying therapies available to HD patients. RNAi is a potentially curative therapy for HD. A popular line of research employs siRNA or antisense oligonucleotides (ASO) to knock down mutant Huntingtin mRNA (mHTT). Unfortunately, this modality requires repeated dosing, commonly exhibit off target effects (OTEs), and exert renal and hepatic toxicity. In contrast, a single AAV-mediated short-hairpin R NA (shRNA) dose can last years with low toxicity. In addition, we highlight research indicating that shRNA elicits fewer OTEs than siRNA when tested head-to-head. Despite this promise, shRNA therapy has been held back by difficulties controlling expression (oversaturating cells with toxic levels of RNA construct). In this review, we compare RNAi modalities for HD and propose novel methods of optimizing shRNA expression and on-target fidelity.
Source: Translational Neurodegeneration - Category: Neurology Source Type: research

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CONCLUSIONS: All patients reported a communication complaint, attested by the DIP scores, despite the fact that not all patients, notably PD, ataxic, and PSP patients, had an intelligibility deficit. The DIP should be used in clinical practice to contribute to a holistic evaluation and management of functional communication in patients with dysarthria. PMID: 31112944 [PubMed - as supplied by publisher]
Source: Neuro-Degenerative Diseases - Category: Neurology Authors: Tags: Neurodegener Dis Source Type: research
Conclusion and Recommendations In this review we attempt to summarize current knowledge about the HD mutation and how information about CAG repeats in the HTT gene can be used to provide sound genetic counseling, which can possibly extend to other neurodegenerative diseases (44). By involving families in observational (i.e., ENROLL-HD platform) and interventional trials, clinicians have an opportunity to include adult patients and their relatives (e.g., partners, symptomatic minors, premanifest adults) in research-based networks that provide current knowledge about developments in genetic testing and novel therapies in HD...
Source: Frontiers in Neurology - Category: Neurology Source Type: research
ConclusionsDifferent patterns of sleep disturbances are observed in HD patients: insomnia, difficulties in falling asleep, frequent nocturnal awakenings, and excessive daytime sleepiness are the most common sleep problems reported by patients with HD. In several HD studies, specific changes in sleep architecture and in circadian melatonin secretion were identified in laboratory testing.Sleep disorders in HD have diverse and complex determinants, the most significant of which includes damage to brain areas that are responsible for the proper sleep pattern and circadian rhythm regulation. Sleep and circadian rhythm disorders...
Source: Frontiers in Psychiatry - Category: Psychiatry Source Type: research
This study underscores the importance of chronic stimulation in the modulation of sensorimotor integration and proprioception. The authors considered two possible mechanisms underlying SAI modulation by STN DBS. High-frequency DBS of the STN might normalize synchronization between basal ganglia structures, which might restore the ability of thalamocortical relay cells to respond to depolarizing inputs involved in sensorimotor integration (Brown et al., 2001; Rubin and Terman, 2004). Alternatively, STN DBS might have a direct effect on cortical structures through antidromic stimulation of the cortico-subthalamic pathway. I...
Source: Frontiers in Human Neuroscience - Category: Neuroscience Source Type: research
Publication date: Available online 17 January 2019Source: Stem Cell ReportsAuthor(s): Zoe Noakes, Francesca Keefe, Claudia Tamburini, Claire M. Kelly, Maria Cruz Santos, Stephen B. Dunnett, Adam C. Errington, Meng LiSummaryStriatal interneurons are born in the medial and caudal ganglionic eminences (MGE and CGE) and play an important role in human striatal function and dysfunction in Huntington's disease and dystonia. MGE/CGE-like neural progenitors have been generated from human pluripotent stem cells (hPSCs) for studying cortical interneuron development and cell therapy for epilepsy and other neurodevelopmental disorders...
Source: Stem Cell Reports - Category: Stem Cells Source Type: research
Authors: Berardelli I, Pasquini M, Conte A, Bologna M, Berardelli A, Fabbrini G Abstract INTRODUCTION: This paper reviews studies that have assessed the treatment of psychiatric disturbances in dystonia, tic disorders, Tourette syndrome, Huntington's disease and essential tremor. Areas covered: We searched for papers in English in Pubmed using the following keywords: blepharospasm, cervical dystonia, arm dystonia, laryngeal dystonia, spasmodic dysphonia, tic disorders, Tourette syndrome, Huntington's chorea, essential tremor, depression, anxiety, obsessive compulsive disorders, attention deficit hyperactivity disorder...
Source: Expert Review of Neurotherapeutics - Category: Neurology Tags: Expert Rev Neurother Source Type: research
CONCLUSIONS: Our in vivo study of the human globus pallidus externus using probabilistic tractography supports the existence of extensive corticopallidal connections and a tripartite functional division, as found in animal studies. A better understanding of the connectivity of the globus pallidus externus may help to understand its function and elucidate the effects of programming the higher contacts in pallidal deep brain stimulation.
Source: American Journal of Neuroradiology - Category: Radiology Authors: Tags: FUNCTIONAL Source Type: research
Credit: New York Times article, Jan. 19, 2016. The United States is in the midst of an opioid overdose epidemic. The rates of opioid addiction, babies born addicted to opioids, and overdoses have skyrocketed in the past decade. No population has been hit harder than rural communities. Many of these communities are in states with historically low levels of funding from the National Institutes of Health (NIH). NIGMS’ Institutional Development Award (IDeA) program builds research capacities in these states by supporting basic, clinical, and translational research, as well as faculty development and infrastructure impro...
Source: Biomedical Beat Blog - National Institute of General Medical Sciences - Category: Research Authors: Tags: Pharmacology Medicines Opioids Pain Source Type: blogs
Abstract Huntington's disease (HD) is an autosomal neurodegenerative disease characterized by chorea, dystonia, motor ataxia, cognitive decline and psychiatric disorders with gradual loss of nerve cells and has no existing cure for the disease. In the present study, a mitochondrial toxin, 3-nitropropionic acid (3-NP) is used to induce HD like symptoms in rats. Tetramethylpyrazine is one of the active ingredients of Chuan Xiong which was reported to have neurotrophic and neuroprotective activities. The present study was designed to evaluate the role of TMP on 3-NP induced behavioral, biochemical, neurochemical, and...
Source: Biomedicine and pharmacotherapy = Biomedecine and pharmacotherapie - Category: Drugs & Pharmacology Authors: Tags: Biomed Pharmacother Source Type: research
Publication date: July 2018Source: Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, Volume 1864, Issue 7Author(s): Stewart F. Graham, Xiaobei Pan, Ali Yilmaz, Shirin Macias, Andrew Robinson, David Mann, Brian D. GreenAbstractHuntington's disease (HD) is a devastating, progressive neurodegenerative disease with a distinct phenotype characterized by chorea and dystonia, incoordination, cognitive decline and behavioral difficulties. The precise mechanisms of HD progression are poorly understood; however, it is known that there is an expansion of the trinucleotide cytosine-adenine-guanine (CAG) repeat in the H...
Source: Biochimica et Biophysica Acta (BBA) Molecular Basis of Disease - Category: Molecular Biology Source Type: research
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