Article
Clinical Neurology
Alexandra Litvinchuk, Tien-Phat Huynh, Yang Shi, Rosemary J. Jackson, Mary B. Finn, Melissa Manis, Caroline M. Francis, Ainsley C. Tran, Patrick M. Sullivan, Jason D. Ulrich, Bradley T. Hyman, Tracy Cole, David M. Holtzman
Summary: Therapeutic reduction of ApoE4 levels through ASO treatment showed significant protective effects on tau pathology, neurodegeneration, neuroinflammation, and synaptic density, indicating a potential therapeutic approach for APOE4 carriers with tauopathy, including Alzheimer's disease.
ANNALS OF NEUROLOGY
(2021)
Review
Pharmacology & Pharmacy
Shivam Kumar Pandey, Rakesh Kumar Singh
Summary: Parkinson's disease is a common neurodegenerative disease that currently can only be managed symptomatically. Nucleic acid-based therapies, such as antisense oligonucleotides and gene therapy, show promise in regulating the genetic dysregulation associated with the disease, specifically the downregulation of the alpha-synuclein gene. This review examines the advancements and limitations of nucleic acid-based therapies for Parkinson's disease.
FRONTIERS IN PHARMACOLOGY
(2022)
Editorial Material
Genetics & Heredity
Muhammad Riaz Khan, Raymund J. Wellinger, Benoit Laurent
Summary: Long noncoding RNA (lncRNA) genes, like protein-coding genes, consist of introns and exons and undergo constitutive and/or alternative splicing after transcription. This review outlines the current understanding of lncRNA splice variants and their functional implications in cell biology.
TRENDS IN GENETICS
(2021)
Article
Chemistry, Multidisciplinary
Ze-Kun Wang, Jia-Le Lin, Yun-Chang Zhang, Chen-Wu Yang, Ya-Kun Zhao, Zheng-Wei Leng, Hui Wang, Dan-Wei Zhang, Jiang Zhu, Zhan-Ting Li
Summary: Five water-soluble flexible organic frameworks were synthesized by quantitatively forming a hydrazone bond in water, displaying tunable diameters and low cytotoxicity. These frameworks can quickly include and deliver DNA into cells, with a delivery rate of up to 99.5%.
MATERIALS CHEMISTRY FRONTIERS
(2021)
Article
Biochemical Research Methods
Helena Chaytow, Ilda Sethw Hassan, Sara Akbar, Linda Popplewell, George Dickson, Philip E. Chen
Summary: The GluA2 subunit of AMPA receptors undergoes RNA editing at a specific site mediated by ADAR2, which is critical for regulating calcium permeability. In this study, PMOs were used to increase editing efficiency by affecting the alternative splicing of ADAR2, leading to enhanced RNA editing of the GluA2 subunit. This method presents a validated approach for investigating downstream cellular processes related to altered ADAR2 activity.
JOURNAL OF NEUROSCIENCE METHODS
(2021)
Review
Biochemistry & Molecular Biology
Craig S. McIntosh, Dunhui Li, Steve D. Wilton, May T. Aung-Htut
Summary: Polyglutamine (polyQ) ataxias are a group of neurological disorders caused by expanded CAG trinucleotide repeats, mainly characterized by progressive ataxia. These disorders are characterized by neuronal aggregations and share common pathogenic mechanisms, with limited therapeutic options available to slow or stop disease progression.
Article
Biochemistry & Molecular Biology
Karima Relizani, Lucia Echevarria, Faouzi Zarrouki, Cecile Gastaldi, Chloe Dambrune, Philippine Aupy, Adrian Haeberli, Marek Komisarski, Thomas Tensorer, Thibaut Larcher, Fedor Svinartchouk, Cyrille Vaillend, Luis Garcia, Aurelie Goyenvalle
Summary: Tricyclo-DNA (tcDNA) is a promising oligonucleotide analog with therapeutic potential, especially when conjugated with palmitic acid for improved delivery to muscle tissues. This conjugation enhances the potency of tcDNA-ASO, resulting in functional improvement in dystrophic mice with significantly reduced dose, while also showing a promising safety profile for clinical development in neuromuscular diseases.
NUCLEIC ACIDS RESEARCH
(2022)
Article
Multidisciplinary Sciences
Taiki Tsurusaki, Kazuki Sato, Hiroki Imai, Kunihiro Hirai, Daisuke Takahashi, Takeshi Wada
Summary: Phosphorodiamidate morpholino oligonucleotides (PMOs) are a promising type of antisense oligonucleotides, but their challenging synthesis makes them difficult to access. This research presents an efficient synthetic approach for PMOs using the H-phosphonate approach. The use of phosphonium-type condensing reagents significantly reduced coupling times compared with the current synthetic approach. This approach would facilitate the large-scale synthesis of PMOs and accelerate their popularity and accessibility as a next-generation therapy.
SCIENTIFIC REPORTS
(2023)
Article
Chemistry, Multidisciplinary
Yu Wang, Shuting Chen, Jingyi Zhang, Qing Ye, Yin Liu
Summary: DNA nanomaterials, as a novel type of nanomaterials, have great potential in biomedical applications due to their high precision, controllability, and biocompatibility. Therapeutic drugs based on DNA nanomaterials have shown beneficial effects on various diseases. However, the instability of DNA nanomaterials greatly hinders their clinical application. In this study, we designed and synthesized a stable topological DNA nanostructure, DNA Nano Trihedron (DNT), which could enter MCF-7 cells without a transfection agent. DNT induced significant changes in gene expression and exhibited significant inhibitory effects on MCF-7 cells. Even after two months of storage, DNT still retained its inhibitory effect on MCF-7 cells.
Article
Multidisciplinary Sciences
Sneha Shah, Kevin J. Sharp, Sithara Raju Ponny, Jonathan Lee, Jonathan K. Watts, Elizabeth Berry- Kravis, Joel D. Richter
Summary: Aberrant alternative splicing of mRNAs leads to dysregulated gene expression in neurological disorders, such as fragile X syndrome (FXS). In this study, the researchers found hundreds of incorrectly expressed and spliced mRNAs in the blood and brain tissues of FXS individuals. They also discovered a previously unknown RNA isoform, FMR1-217, which is generated through mis-splicing of the FMR1 gene in FXS tissues. Treatment with antisense oligonucleotides (ASOs) could reduce FMR1-217 and restore normal gene expression and protein levels. These findings suggest that RNA-processing events in blood could serve as biomarkers for FXS and ASO treatment may be a potential therapy.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Article
Chemistry, Multidisciplinary
Yaxian Zhou, Peng Teng, Nathan T. Montgomery, Xiaolei Li, Weiping Tang
Summary: Targeted protein degradation (TPD) technology has become a focus of attention for researchers due to its potential as a new therapeutic modality and selective removal of various protein targets. Specifically, LYsosome TArgeting Chimera (LYTAC) has emerged as a promising technology for degrading extracellular protein targets, using the cation-independent mannose-6-phosphate receptor (CI-M6PR) to deliver them to lysosomes. This study successfully utilized the asialoglycoprotein receptor (ASGPR) expressed on liver cells, with the ligand triantennary N-acetylgalactosamine (tri-GalNAc), to target extracellular proteins for degradation, demonstrating cell type specificity in liver cell lines.
ACS CENTRAL SCIENCE
(2021)
Article
Chemistry, Analytical
Zifan Li, Fei Tong, Li Xiao, Nicholas R. Larson, Xuan Zhou, Yueheng Zhang, Jonas P. Immel-Brown, George M. Bou-Assaf
Summary: This study presents a novel protocol for detecting stereochemical changes in phosphorothioate oligonucleotides, using nuclease P1 digestion followed by LCMS analysis. The method is valuable for establishing stereochemical comparability and ensuring manufacturing consistency of oligonucleotide therapeutics.
Article
Audiology & Speech-Language Pathology
Katelyn N. Robillard, Erik de Vrieze, Erwin van Wijk, Jennifer J. Lentz
Summary: Hearing loss, affecting over 430 million people worldwide, has significant impacts on physical, cognitive, and overall well-being. Antisense oligonucleotide (ASO)-based therapies show promise in treating hereditary hearing loss disorders by manipulating gene expression and targeting specific genetic factors.
Review
Chemistry, Multidisciplinary
Hao Cui, Xinying Zhu, Shuyue Li, Peipei Wang, Jianping Fang
Summary: The potential therapeutic application of oligonucleotides that selectively suppress target genes through antisense and RNA interference mechanisms has attracted widespread attention, with a focus on liver-targeted delivery using N-acetylgalactosamine (GalNAc) ligands. Recent progress in the field of GalNAc conjugates for improving cellular uptake and tissue-specific delivery has shown promising results in preclinical and clinical trials.
Article
Chemistry, Analytical
Toshitsugu Fujita, Shoko Nagata, Hodaka Fujii
Summary: Blocking PCR is a method to selectively inhibit the amplification of wild-type DNA while amplifying mutated DNA by using a nucleotide sequence complementary to a blocker. Our study demonstrates that an oligoribonucleotide (ORN) can effectively suppress the extension of target DNA by Taq DNA polymerases. This method has been successfully applied for real-time ORNi-PCR and one-step real-time reverse transcriptionORNi-PCR to detect single-nucleotide mutations in DNA and RNA in a sequence-specific manner, providing technical insights for further improvement of blocking PCR.
ANALYTICAL CHEMISTRY
(2023)
Article
Psychology, Clinical
Akshay Nair, Ritwik K. Niyogi, Fei Shang, Sarah J. Tabrizi, Geraint Rees, Robb B. Rutledge
Summary: This study provides new insights into understanding and explaining apathy, a disabling neuropsychiatric symptom, by investigating the relationship between the opportunity cost of time (OCT), self-initiation, and apathy. The findings suggest that OCT is an important variable for determining free-operant action initiation and understanding apathy.
PSYCHOLOGICAL MEDICINE
(2023)
Article
Clinical Neurology
Sarah J. Tabrizi, Carlos Estevez-Fraga, Willeke M. C. van Roon-Mom, Michael D. Flower, Rachael I. Scahill, Edward J. Wild, Ignacio Munoz-Sanjuan, Cristina Sampaio, Anne E. Rosser, Blair R. Leavitt
Summary: Huntington's disease is a prevalent neurodegenerative disorder with complex molecular pathogenesis. Currently, there is no effective treatment available. Potential interventions include targeting huntingtin DNA and RNA, clearing huntingtin protein, and DNA repair pathways. Evaluating past trials and considering the current situation will help in addressing the challenges and opportunities for the future.
Article
Clinical Neurology
Sarah J. Tabrizi, Scott Schobel, Emily C. Gantman, Alexandra Mansbach, Beth Borowsky, Pavlina Konstantinova, Tiago A. Mestre, Jennifer Panagoulias, Christopher A. Ross, Maurice Zauderer, Ariana P. Mullin, Klaus Romero, Sudhir Sivakumaran, Emily C. Turner, Jeffrey D. Long, Cristina Sampaio
Summary: The current research paradigm for Huntington's disease does not address its pathophysiology nor the biomarker changes that can precede the functional decline by decades. This study introduces a new research framework, the Huntington's Disease Integrated Staging System, to standardise clinical research and enable interventions earlier in the disease course.
Article
Clinical Neurology
Gustavo L. Franklin, Helio A. G. Teive, Alex T. Meira, Adriana M. T. Nepomuceno, Sarah J. Tabrizi
Summary: The article "On Chorea" by George Huntington was published in The Medical and Surgical Reporter of Philadelphia on April 13, 1872. It is a significant milestone in the recognition of Huntington's chorea, a disease that later became named after him. However, there are still some myths and curiosities surrounding the history of this publication and its author.
MOVEMENT DISORDERS
(2022)
Article
Neurosciences
Carlos Estevez-Fraga, Sarah J. Tabrizi, Edward J. Wild
Summary: This article provides an in-depth overview of the PIVOT HD and SIGNAL trials in Huntington's disease, along with a comprehensive list of all currently registered and ongoing clinical trials. It also includes a "breaking news" section highlighting recent updates on the SELECT HD, uniQure AMT-130, and VIBRANT HD clinical trials.
JOURNAL OF HUNTINGTONS DISEASE
(2022)
Article
Neurosciences
Jenny Lange, Olivia Gillham, Michael Flower, Heather Ging, Simon Eaton, Sneha Kapadia, Andreas Neueder, Michael R. Duchen, Patrizia Ferretti, Sarah J. Tabrizi
Summary: Huntington's Disease is a neurodegenerative disease caused by a genetic mutation. Astrocyte dysfunction, specifically changes in gene expression and metabolic activity, plays a role in the pathogenesis of the disease. Additionally, all Huntington's Disease astrocytes exhibit increased DNA damage and a DNA damage response, suggesting a potential mechanism for their dysfunction.
PROGRESS IN NEUROBIOLOGY
(2023)
Article
Behavioral Sciences
Carlos Estevez-Fraga, Michael S. Elmalem, Marina Papoutsi, Alexandra Durr, Elin M. Rees, Nicola Z. Hobbs, Raymund A. C. Roos, Bernhard Landwehrmeyer, Blair R. Leavitt, Douglas R. Langbehn, Rachael I. Scahill, Geraint Rees, Sarah J. Tabrizi, Sarah Gregory
Summary: This study investigated the longitudinal changes in white matter microstructure in Huntington's disease and found significant alterations in larger white matter areas as the disease progressed, indicating a progressive deterioration of white matter microstructure with disease evolution.
BRAIN AND BEHAVIOR
(2023)
Editorial Material
Neurosciences
Mena Farag, Desiree M. Salanio, Cara Hearst, Daniela Rae, Sarah J. Tabrizi
Summary: Advance care planning (ACP) is a beneficial tool that allows adult patients to express and formalize their beliefs, preferences, and wishes regarding future medical care. For Huntington's disease (HD) patients, early consideration of ACP is crucial due to challenges in determining decision-making capacity in the later stages of the disease. ACP empowers patients and provides reassurance to clinicians and surrogate decision makers by ensuring that medical management aligns with the patient's expressed wishes. Regular follow-up is necessary to maintain consistency in decisions and wishes. We outline the framework of our dedicated ACP clinic within the HD service, emphasizing the importance of patient-centered and personalized care plans that reflect the patient's goals, preferences, and values.
JOURNAL OF HUNTINGTONS DISEASE
(2023)
Article
Clinical Neurology
Andreas-Antonios Roussakis, Marta Gennaro, Mark Forrest Gordon, Ralf Reilmann, Beth Borowsky, Gail Rynkowski, Nicholas P. Lao-Kaim, Zoe Papoutsou, Juha-Matti Savola, Michael R. Hayden, David R. Owen, Nicola Kalk, Anne Lingford-Hughes, Roger N. Gunn, Graham Searle, Sarah J. Tabrizi, Paola Piccini
Summary: This longitudinal study demonstrates that the treatment of laquinimod in Huntington's disease does not affect regional microglia activation. Microglia activation is believed to be related to inflammation in the central nervous system and the progression of Huntington's disease. However, laquinimod is capable of regulating microglia. The study also shows that C-11-PBR28 PET-CT imaging can be used to assess regional gliosis and the effects of laquinimod treatment.
BRAIN COMMUNICATIONS
(2023)
Review
Biochemistry & Molecular Biology
Sangeerthana Rajagopal, Jasmine Donaldson, Michael Flower, Davina J. Hensman Moss, Sarah J. Tabrizi
Summary: Repeat expansion disorders (REDs) are monogenic diseases caused by repetitive DNA sequences expanding beyond a pathogenic threshold. The length of the repeat sequence is a major determinant of age at onset and disease progression. Phenotypic variability in REDs is influenced by factors such as the gene involved, the location of the repeat sequence, and the presence of interruptions. DNA repair pathways have been identified as potential modifiers of RED phenotypes, offering potential targets for disease-modifying therapies.
EMERGING TOPICS IN LIFE SCIENCES
(2023)
Article
Clinical Neurology
Chin-Fu Liu, Laurent Younes, Xiao J. Tong, Jared T. Hinkle, Maggie Wang, Sanika Phatak, Xin Xu, Xuan Bu, Vivian Looi, Jee Bang, Sarah J. Tabrizi, Rachael Scahill, Jane S. Paulsen, Nellie Georgiou-Karistianis, Andreia Faria, Michael Miller, J. Tilak Ratnanather, Christopher A. Ross
Summary: Huntington's disease is caused by a CAG repeat expansion in the Huntingtin gene, resulting in increased polyglutamine in the Huntingtin protein. This study analyzed three longitudinal datasets and found significant selective atrophy in multiple regions, supporting the hypothesis of circuit-based spread of pathology in Huntington's disease.
BRAIN COMMUNICATIONS
(2023)
Meeting Abstract
Clinical Neurology
Robert Goold, Joseph Hamilton, Thomas Menneteau, Michael Flower, Emma Bunting, Sarah Aldous, Antonio Porro, Jose Vicente, Nicholas Allen, Hilary Wilkinson, Gillian Bates, Alessandro Sartori, Konstantinos Thalassinos, Gabriel Balmus, Sarah Tabrizi
JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY
(2022)
Meeting Abstract
Clinical Neurology
Harry D. J. Knights, Annabelle Coleman, Nicola Z. Hobbs, Sarah J. Tabrizi, Rachael I. Scahill
JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY
(2022)
Meeting Abstract
Clinical Neurology
Maitrei Kohli, Dorian Pustina, John H. Warner, Daniel C. Alexander, Rachael I. Scahill, Sarah J. Tabrizi, Peter A. Wijeratne
JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY
(2022)
Meeting Abstract
Clinical Neurology
Davina Hensman Moss, Anupriya Dalmia, Valentina Galassi Deforie, Kristina Ibanez, Sarah J. Tabrizi, Nayana Lahiri, Henry Houlden, Peter Holmans, Lesley Jones, Arianna Tucci
JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY
(2022)
