{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T19:22:48Z","timestamp":1792264968287,"version":"4.4.0"},"reference-count":57,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2020,3,20]],"date-time":"2020-03-20T00:00:00Z","timestamp":1584662400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Trials using antisense oligonucleotide technology to lower Huntingtin levels in Huntington\u2019s disease (HD) are currently ongoing. This progress, taking place only 27 years after the identification of the Huntingtin gene (HTT) in 1993 reflects the enormous development in genetic engineering in the last decades. It is also the result of passionate basic scientific work and large worldwide registry studies that have advanced the understanding of HD. Increased knowledge of the pathophysiology of this autosomal dominantly inherited CAG-repeat expansion mediated neurodegenerative disease has led to the development of several putative treatment strategies, currently under investigation. These strategies span the whole spectrum of potential targets from genome editing via RNA interference to promoting protein degradation. Yet, recent studies revealed the importance of huntingtin RNA in the pathogenesis of the disease. Therefore, huntingtin-lowering by means of RNA interference appears to be a particular promising strategy. As a matter of fact, these approaches have entered, or are on the verge of entering, the clinical trial period. Here, we provide an overview of huntingtin-lowering approaches via DNA or RNA interference in present clinical trials as well as strategies subject to upcoming therapeutic options. We furthermore discuss putative implications for future treatment of HD patients.<\/jats:p>","DOI":"10.3390\/ijms21062146","type":"journal-article","created":{"date-parts":[[2020,3,20]],"date-time":"2020-03-20T11:42:11Z","timestamp":1584704531000},"page":"2146","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":45,"title":["Huntingtin Lowering Strategies"],"prefix":"10.3390","volume":"21","author":[{"given":"Franz","family":"Marxreiter","sequence":"first","affiliation":[{"name":"Huntington\u2019s Disease Outpatient Clinic, Department of Molecular Neurology, University Hospital Erlangen, Schwabachanlage 6, 91054 Erlangen, Germany"},{"name":"Center for Rare Movement Disorders, Department of Molecular Neurology, University Hospital Erlangen, Schwabachanlage 6, 91054 Erlangen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Judith","family":"Stemick","sequence":"additional","affiliation":[{"name":"Huntington\u2019s Disease Outpatient Clinic, Department of Molecular Neurology, University Hospital Erlangen, Schwabachanlage 6, 91054 Erlangen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4147-8866","authenticated-orcid":false,"given":"Zacharias","family":"Kohl","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Regensburg, Universit\u00e4tsstra\u00dfe 84, 93053 Regensburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,3,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"c3109","DOI":"10.1136\/bmj.c3109","article-title":"Huntington\u2019s disease","volume":"340","author":"Novak","year":"2010","journal-title":"BMJ"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"360","DOI":"10.1136\/pn.2007.134585","article-title":"The differential diagnosis of chorea","volume":"7","author":"Wild","year":"2007","journal-title":"Pract. Neurol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1111\/ene.13413","article-title":"Huntington\u2019s disease: A clinical review","volume":"25","author":"McColgan","year":"2018","journal-title":"Eur. J. Neurol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1212\/01.wnl.0000198586.85250.13","article-title":"Tetrabenazine as antichorea therapy in Huntington disease: A randomized controlled trial","volume":"66","author":"Marshall","year":"2006","journal-title":"Neurology"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1159\/000443738","article-title":"The Prevalence of Huntington\u2019s disease","volume":"46","author":"Rawlins","year":"2016","journal-title":"Neuroepidemiology"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Bates, G., Tabrizi, S., and Jones, L. (2014). Huntington\u2019s Disease, Oxford University Press.","DOI":"10.1093\/med\/9780199929146.001.0001"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"650","DOI":"10.1001\/jamaneurol.2019.0423","article-title":"Prevalence of carriers of intermediate and pathological polyglutamine disease\u2013associated alleles among large population-based cohorts","volume":"76","author":"Gardiner","year":"2019","journal-title":"JAMA Neurol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/S1474-4422(10)70245-3","article-title":"Huntington\u2019s disease: From molecular pathogenesis to clinical treatment","volume":"10","author":"Ross","year":"2011","journal-title":"Lancet Neurol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"650","DOI":"10.1016\/j.brainres.2016.03.034","article-title":"Endoplasmic reticulum stress: The cause and solution to Huntington\u2019s disease?","volume":"1648","author":"Jiang","year":"2016","journal-title":"Brain Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"8808","DOI":"10.1074\/jbc.M109.075028","article-title":"Proteolysis of Mutant Huntingtin Produces an Exon 1 Fragment That Accumulates as an Aggregated Protein in Neuronal Nuclei in Huntington Disease","volume":"285","author":"Landles","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"690","DOI":"10.1212\/WNL.0b013e318249f683","article-title":"CAG repeat expansion in Huntington disease determines age at onset in a fully dominant fashion","volume":"78","author":"Lee","year":"2012","journal-title":"Neurology"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"887","DOI":"10.1016\/j.cell.2019.06.036","article-title":"CAG Repeat Not Polyglutamine Length Determines Timing of Huntington\u2019s Disease Onset","volume":"178","author":"Consortium","year":"2019","journal-title":"Cell"},{"key":"ref_13","unstructured":"Genetic Modifiers of Huntington\u2019s Disease (GeM-HD) Consortium (2015). Identification of Genetic Factors that Modify Clinical Onset of Huntington\u2019s disease. Cell, 162, 516\u2013526."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"17","DOI":"10.3389\/fnhum.2017.00017","article-title":"Contribution of neuroepigenetics to Huntington\u2019s disease","volume":"11","author":"Francelle","year":"2017","journal-title":"Front. Hum. Neurosci."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"101","DOI":"10.3233\/JHD-180292","article-title":"A Fresh Look at Huntingtin mRNA Processing in Huntington\u2019s Disease","volume":"7","author":"Romo","year":"2018","journal-title":"J. Huntingt. Dis."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"8653132","DOI":"10.1155\/2016\/8653132","article-title":"Review Article Neuroimmunology of Huntington\u2019s Disease: Revisiting Evidence from Human Studies","volume":"2016","author":"Rocha","year":"2016","journal-title":"Mediat. Inflamm."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Vale, T.C., and Cardoso, F. (2015). Chorea: A Journey Throughout History. Tremor Other Hyperkinet. Mov., 5.","DOI":"10.5334\/tohm.275"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"905","DOI":"10.1016\/0092-8674(91)90397-H","article-title":"Identification of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome","volume":"65","author":"Verkerk","year":"1991","journal-title":"Cell"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"971","DOI":"10.1016\/0092-8674(93)90585-E","article-title":"A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington\u2019s disease chromosomes","volume":"72","author":"MacDonald","year":"1993","journal-title":"Cell"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1016\/S0092-8674(00)81369-0","article-title":"Exon 1 of the HD Gene with an Expanded CAG Repeat Is Sufficient to Cause a Progressive Neurological Phenotype in Transgenic Mice","volume":"87","author":"Mangiarini","year":"1996","journal-title":"Cell"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/S0092-8674(00)80623-6","article-title":"Reversal of Neuropathology and Motor Dysfunction in a Conditional Model of Huntington\u2019s disease","volume":"101","author":"Yamamoto","year":"2000","journal-title":"Cell"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"5820","DOI":"10.1073\/pnas.0501507102","article-title":"RNA interference improves motor and neuropathological abnormalities in a Huntington\u2019s disease mouse model","volume":"102","author":"Harper","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1031","DOI":"10.1016\/j.neuron.2012.05.009","article-title":"Sustained therapeutic reversal of Huntington\u2019s disease by transient repression of huntingtin synthesis","volume":"76","author":"Kordasiewicz","year":"2012","journal-title":"Neuron"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"964","DOI":"10.1016\/j.neuron.2012.06.001","article-title":"\u201cHuntingtin Holiday\u201d: Progress toward an Antisense Therapy for Huntington\u2019s disease","volume":"74","author":"Lu","year":"2012","journal-title":"Neuron"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"12116","DOI":"10.1038\/srep12166","article-title":"Ultrasensitive measurement of huntingtin protein in cerebrospinal fluid demonstrates increase with Huntington disease stage and decrease following brain huntingtin suppression","volume":"5","author":"Southwell","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1979","DOI":"10.1172\/JCI80743","article-title":"Quantification of mutant huntingtin protein in cerebrospinal fluid from Huntington\u2019s disease patients","volume":"125","author":"Wild","year":"2015","journal-title":"J. Clin. Investig."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"eaat7108","DOI":"10.1126\/scitranslmed.aat7108","article-title":"Evaluation of mutant huntingtin and neurofilament proteins as potential markers in Huntington\u2019s disease","volume":"10","author":"Byrne","year":"2018","journal-title":"Sci. Transl. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1016\/j.expneurol.2011.11.020","article-title":"Widespread suppression of huntingtin with convection-enhanced delivery of siRNA","volume":"233","author":"Stiles","year":"2012","journal-title":"Exp. Neurol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2152","DOI":"10.1038\/mt.2011.219","article-title":"Preclinical Safety of RNAi-Mediated HTT Suppression in the Rhesus Macaque as a Potential Therapy for Huntington\u2019s Disease","volume":"19","author":"McBride","year":"2016","journal-title":"Mol. Ther."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1016\/j.neuron.2019.02.017","article-title":"Therapeutic AAV Gene Transfer to the Nervous System: A Clinical Reality","volume":"101","author":"Hudry","year":"2019","journal-title":"Neuron"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"478","DOI":"10.1089\/hum.2016.087","article-title":"Adeno-Associated Virus-Based Gene Therapy for CNS Diseases","volume":"27","author":"Hocquemiller","year":"2016","journal-title":"Hum. Gene Ther."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1723","DOI":"10.1056\/NEJMoa1702752","article-title":"Nusinersen versus Sham Control in Infantile-Onset Spinal Muscular Atrophy","volume":"377","author":"Finkel","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1056\/NEJMoa1716793","article-title":"Inotersen Treatment for Patients with Hereditary Transthyretin Amyloidosis","volume":"379","author":"Benson","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2307","DOI":"10.1056\/NEJMoa1900907","article-title":"Targeting Huntingtin Expression in Patients with Huntington\u2019s Disease","volume":"380","author":"Tabrizi","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2495","DOI":"10.1212\/WNL.0000000000004743","article-title":"Motor, cognitive, and functional declines contribute to a single progressive factor in early HD","volume":"89","author":"Schobel","year":"2017","journal-title":"Neurology"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"774","DOI":"10.1016\/j.cub.2009.03.030","article-title":"Five siRNAs Targeting Three SNPs May Provide Therapy for Three-Quarters of Huntington\u2019s Disease Patients","volume":"19","author":"Pfister","year":"2009","journal-title":"Curr. Biol."},{"key":"ref_37","unstructured":"(2020, February 14). HDSA. Available online: https:\/\/hdsa.org\/news\/wave-life-sciences-announces-topline-data-and-addition-of-higher-dose-cohort-in-ongoing-phase-1b-2a-precision-hd2-trial-in-huntingtons-disease\/."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"884","DOI":"10.1038\/s41587-019-0205-0","article-title":"A divalent siRNA chemical scaffold for potent and sustained modulation of gene expression throughout the central nervous system","volume":"37","author":"Alterman","year":"2019","journal-title":"Nat. Biotechnol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"e297","DOI":"10.1038\/mtna.2016.7","article-title":"Design, characterization, and lead selection of therapeutic miRNAs targeting Huntingtin for development of gene therapy for Huntington\u2019s disease","volume":"5","author":"Miniarikova","year":"2016","journal-title":"Mol. Ther. Nucleic Acids"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1016\/j.omtm.2019.09.010","article-title":"AAV5-miHTT Lowers Huntingtin mRNA and Protein without Off-Target Effects in Patient-Derived Neuronal Cultures and Astrocytes","volume":"15","author":"Keskin","year":"2019","journal-title":"Mol. Ther. Methods Clin. Dev."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1089\/hum.2013.200","article-title":"Silencing Mutant Huntingtin by Adeno-Associated Virus-Mediated RNA Interference Ameliorates Disease Manifestations in the YAC128 Mouse Model of Huntington\u2019s Disease","volume":"25","author":"Stanek","year":"2014","journal-title":"Hum. Gene Ther."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1131","DOI":"10.1038\/s41591-019-0478-3","article-title":"Allele-selective transcriptional repression of mutant HTT for the treatment of Huntington\u2019s disease","volume":"25","author":"Zeitler","year":"2019","journal-title":"Nat. Med."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1016\/j.neuron.2019.01.039","article-title":"Huntingtin Lowering Strategies for Disease Modification in Huntington\u2019s disease","volume":"101","author":"Tabrizi","year":"2019","journal-title":"Neuron"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1038\/nrneurol.2017.148","article-title":"Antisense oligonucleotides: The next frontier for treatment of neurological disorders","volume":"14","author":"Rinaldi","year":"2018","journal-title":"Nat. Rev. Neurol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"21599","DOI":"10.1074\/jbc.M112.359307","article-title":"Proteomic Analysis of Wild-type and Mutant Huntingtin-associated Proteins in Mouse Brains Identifies Unique Interactions and Involvement in Protein Synthesis","volume":"287","author":"Culver","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1038\/81593","article-title":"Inactivation of Hdh in the brain and testis results in progressive neurodegeneration and sterility in mice","volume":"26","author":"Dragatsis","year":"2000","journal-title":"Nat. Genet."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"3359","DOI":"10.1073\/pnas.1524575113","article-title":"Ablation of huntingtin in adult neurons is nondeleterious but its depletion in young mice causes acute pancreatitis","volume":"113","author":"Wang","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3233\/JHD-170235","article-title":"Is Huntingtin Dispensable in the Adult Brain?","volume":"6","author":"Liu","year":"2017","journal-title":"J. Huntingt. Dis."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1197","DOI":"10.1093\/brain\/awr333","article-title":"Six-month partial suppression of Huntingtin is well tolerated in the adult rhesus striatum","volume":"135","author":"Grondin","year":"2012","journal-title":"Brain"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1112","DOI":"10.1016\/j.ajhg.2019.10.011","article-title":"A Comprehensive Haplotype-Targeting Strategy for Allele-Specific HTT Suppression in Huntington Disease","volume":"105","author":"Kay","year":"2019","journal-title":"Am. J. Hum. Genet."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1644","DOI":"10.1056\/NEJMoa1813279","article-title":"Patient-Customized Oligonucleotide Therapy for a Rare Genetic Disease","volume":"381","author":"Kim","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1111\/cge.12385","article-title":"Personalized gene silencing therapeutics for Huntington disease","volume":"86","author":"Kay","year":"2014","journal-title":"Clin. Genet."},{"key":"ref_53","unstructured":"(2020, February 14). Gemeinsamer Bundesausschuss. Available online: https:\/\/www.g-ba.de\/downloads\/40&#x2013;268&#x2013;4722\/2017&#x2013;12&#x2013;21_AM-RL-XII_Nusinersen_D&#x2013;294_TrG.pdf."},{"key":"ref_54","unstructured":"(2020, February 14). Gemeinsamer Bundesausschuss. Available online: https:\/\/www.g-ba.de\/bewertungsverfahren\/nutzenbewertung\/389\/."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1111\/j.1399-0004.2004.00241.x","article-title":"A new model for prediction of the age of onset and penetrance for Huntington\u2019s disease based on CAG length","volume":"65","author":"Langbehn","year":"2004","journal-title":"Clin. Genet."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1002\/ajmg.b.31232","article-title":"Indexing disease progression at study entry with individuals at-risk for Huntington disease","volume":"156","author":"Zhang","year":"2011","journal-title":"Am. J. Med. Genet. Part B: Neuropsychiatr. Genet."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1002\/mds.26838","article-title":"Validation of a prognostic index for Huntington\u2019s disease","volume":"32","author":"Long","year":"2017","journal-title":"Mov. Disord."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/6\/2146\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:10:11Z","timestamp":1760173811000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/6\/2146"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,3,20]]},"references-count":57,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2020,3]]}},"alternative-id":["ijms21062146"],"URL":"https:\/\/doi.org\/10.3390\/ijms21062146","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,3,20]]}}}