Sustained Therapeutic Reversal of Huntington's Disease by Transient Repression of Huntingtin Synthesis
Open accessAbstract
The primary cause of Huntington's disease (HD) is expression of huntingtin with a polyglutamine expansion. Despite an absence of consensus on the mechanism(s) of toxicity, diminishing the synthesis of mutant huntingtin will abate toxicity if delivered to the key affected cells. With antisense oligonucleotides (ASOs) that catalyze RNase H-mediated degradation of huntingtin mRNA, we demonstrate that transient infusion into the cerebrospinal fluid of symptomatic HD mouse models not only delays disease progression but mediates a sustained reversal of disease phenotype that persists longer than the huntingtin knockdown. Reduction of wild-type huntingtin, along with mutant huntingtin, produces the same sustained disease reversal. Similar ASO infusion into nonhuman primates is shown to effectively lower huntingtin in many brain regions targeted by HD pathology. Rather than requiring continuous treatment, our findings establish a therapeutic strategy for sustained HD disease reversal produced by transient ASO-mediated diminution of huntingtin synthesis.
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ASOs are not well suited for deep brain structure targets.
“numerous studies suggest that ASOs are not well suited for deep brain structure targets [16,47,52].”
From Elucidating brain transport pathways and cell type-dependent gene silencing of a durable lipid–siRNA conjugate administered into cerebrospinal fluid (2025) · cites this paper as [16]
The Results (page unavailable) report ASO accumulation in the mouse striatum, thalamus, midbrain, and brainstem, with significant huntingtin suppression in those regions. Although the reported reduction in the primate caudate was not statistically significant, the Discussion (page unavailable) describes ASO infusion as effective and capable of targeting many brain regions. The paper therefore makes a contrary point to the broad claim that ASOs are not well suited to deep-brain targets. (LLM, conf=0.86)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredASO delivery to deep brain structures is limited, with no significant HTT silencing observed in NHP caudate after multiple injections.
“However, ASO delivery to deep brain structures is limited4, with no significant HTT silencing observed in NHP caudate after multiple injections42.”
From A divalent siRNA chemical scaffold for potent and sustained modulation of gene expression throughout the central nervous system (2019) · cites this paper as [4]
The Results section (‘Suppression of huntingtin levels in the CNS after ASO infusion into non-human primates’; page not provided) reports that caudate huntingtin mRNA trended toward a 25% reduction, but the result was not statistically significant (p=0.23). The study used continuous infusion into the cerebrospinal fluid for 21 days, not multiple injections. The separate claim about limited delivery to deep brain structures is attached to citation 4, not this source. (LLM, conf=0.90)
Experimental — accuracy not yet measuredASO injection into CSF is a therapeutically viable approach that was initiated 14 years ago and validated to yield effective delivery to neurons and glial cells throughout the rodent and non-human primate nervous systems.
“ASO injection into cerebral spinal fluid (CSF) is a therapeutically viable approach that was initiated 14 years ago13 and validated to yield effective delivery to neurons and glial cells throughout the rodent13 and non-human primate14 nervous systems.”
From Therapeutically viable generation of neurons with antisense oligonucleotide suppression of PTB (2021) · cites this paper as [14]
The Results section on non-human primates reports that ASOs infused into rhesus monkeys’ CSF reached neurons across many brain and spinal-cord regions and reduced huntingtin mRNA. It does not establish delivery to glial cells in the primates; the reported astrocyte uptake appears in the separate rodent results. The ‘14 years ago’ and rodent portions of the sentence are attached to citation 13, not this source’s citation 14. (LLM, conf=0.84)
Experimental — accuracy not yet measuredOptimized ASOs to other targets have previously been shown to yield dose dependent target RNA suppression to 5% of initial level.
“optimized ASOs to other targets have previously been shown to yield dose dependent target RNA suppression to 5% of initial level13,14,48.”
From Therapeutically viable generation of neurons with antisense oligonucleotide suppression of PTB (2021) · cites this paper as [14]
The Results section reports dose-dependent suppression of human huntingtin mRNA by an ASO, to 42% and 28% of vehicle levels at the two doses tested. It does not report suppression to 5% of initial levels or establish that result for other targets. (LLM, conf=0.88)
Experimental — accuracy not yet measuredASOs can specifically alter levels and/or processing of a variety of proteins involved in neurodegenerative diseases, most of which have been the disease-causing protein itself.
“Due to the precision afforded by complementary binding of an ASO to its target transcript of interest, ASOs have emerged as an invaluable tool in specifically altering levels and/or processing of a variety of proteins involved in neurodegenerative diseases, most of which have been the disease-causing protein itself (38, 51–54).”
From Reduction of nemo-like kinase increases lysosome biogenesis and ameliorates TDP-43–related neurodegeneration (2023) · cites this paper as [52]
Injection of ASOs into the CSF represents another promising method to silence neuronal gene expression in vivo.
“Injection of ASOs into the CSF represents another promising method to silence neuronal gene expression in vivo.25”
From Lipid Nanoparticle Delivery of siRNA to Silence Neuronal Gene Expression in the Brain (2013) · cites this paper as [25]
Such conjugated siRNAs are retained near the brain injection site, even with continuous monthly administration.
“However, they are retained near the brain injection site, even with continuous monthly administration4, 7.”
From A divalent siRNA chemical scaffold for potent and sustained modulation of gene expression throughout the central nervous system (2019) · cites this paper as [4]
The Results section on ASO distribution (page unavailable) reports that infused antisense oligonucleotides reached many brain regions, rather than remaining near the injection site. But the claim concerns conjugated siRNAs under continuous monthly administration; our copy does not report that treatment or its distribution. Searches for conjugated siRNAs and monthly administration found no passage addressing it. (LLM, conf=0.76)
Experimental — accuracy not yet measuredSimilar ASO mRNA-targeted approaches have improved disease phenotypes in rat models of SOD1-related ALS, mouse models of Huntington's disease and FTDP-17, and in C9ORF72 patient-derived cell lines.
“Similar ASO mRNA-targeted approaches have improved disease phenotypes in rat models of superoxide dismutase 1 (SOD1)-related ALS (17), mouse models of Huntington’s disease (18) and FTDP-17 (19), and in C9ORF72 patient-derived cell lines (20, 21).”
From Tau reduction prevents neuronal loss and reverses pathological tau deposition and seeding in mice with tauopathy (2017) · cites this paper as [18]
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Cites
MACDONALD, M. (1993) · Cell · doi:10.1016/0092-8674(93)90585-e · Cited by 8,366 · see citing works
Onset and Progression in Inherited ALS Determined by Motor Neurons and Microglia
Boillée, S., Yamanaka, K., Lobsiger, C. S., Copeland, N. G., Jenkins, N. A., Kassiotis, G., Kollias, G., & Cleveland, D. W. (2006) · Science · doi:10.1126/science.1123511 · Cited by 1,623 · see citing works
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Research works printed but not linked: 47
- Bennett CF Swayze EE 2010 RNA targeting therapeutics: molecular mechanisms of antisense oligonucleotides as a therapeutic platform Annu Rev Pharmacol Toxicol 50 259 293 20055705
- Boudreau RL McBride JL Martins I Shen S Xing Y Carter BJ Davidson BL 2009 Nonallele-specific silencing of mutant and wild-type huntingtin demonstrates therapeutic efficacy in Huntington’s disease mice Mol Ther 17 1053 1063 19240687 PMC2835182
- Brooks E Arrasate M Cheung K Finkbeiner SM 2004 Using antibodies to analyze polyglutamine stretches Methods Mol Biol 277 103 128 15201452
- Carroll JB Warby SC Southwell AL Doty CN Greenlee S Skotte N Hung G Bennett CF Freier SM Hayden MR 2011 Potent and selective antisense oligonucleotides targeting single-nucleotide polymorphisms in the huntington disease gene/allele-specific silencing of mutant huntingtin Mol Ther 19 2178 2185 21971427 PMC3242664
- Cerritelli SM Crouch RJ 2009 Ribonuclease H: the enzymes in eukaryotes FEBS J 276 1494 1505 19228196 PMC2746905
- Cheruvallath ZS Kumar RK Rentel C Cole DL Ravikumar VT 2003 Solid phase synthesis of phosphorothioate oligonucleotides utilizing diethyldithiocarbonate disulfide (DDD) as an efficient sulfur transfer reagent Nucleosides Nucleotides Nucleic Acids 22 461 468 12885126
- Crooke ST 1999 Molecular mechanisms of action of antisense drugs Biochim Biophys Acta 1489 31 44 10806995
- de la Monte SM Vonsattel JP Richardson EP Jr 1988 Morphometric demonstration of atrophic changes in the cerebral cortex, white matter, and neostriatum in Huntington’s disease J Neuropathol Exp Neurol 47 516 525 2971785
- Denovan-Wright EM Rodriguez-Lebron E Lewin AS Mandel RJ 2008 Unexpected off-targeting effects of anti-huntingtin ribozymes and siRNA in vivo Neurobiol Dis 29 446 455 18166484 PMC2695881
- Diaz-Hernandez M Torres-Peraza J Salvatori-Abarca A Moran MA Gomez-Ramos P Alberch J Lucas JJ 2005 Full motor recovery despite striatal neuron loss and formation of irreversible amyloid-like inclusions in a conditional mouse model of Huntington’s disease J Neurosci 25 9773 9781 16237181 PMC6725739
- DiFiglia M Sena-Esteves M Chase K Sapp E Pfister E Sass M Yoder J Reeves P Pandey RK Rajeev KG 2007 Therapeutic silencing of mutant huntingtin with siRNA attenuates striatal and cortical neuropathology and behavioral deficits Proc Natl Acad Sci U S A 104 17204 17209 17940007 PMC2040405
- Dragatsis I Levine MS Zeitlin S 2000 Inactivation of Hdh in the brain and testis results in progressive neurodegeneration and sterility in mice Nat Genet 26 300 306 11062468
- Drouet V Perrin V Hassig R Dufour N Auregan G Alves S Bonvento G Brouillet E Luthi-Carter R Hantraye P Deglon N 2009 Sustained effects of nonallele-specific Huntingtin silencing Ann Neurol 65 276 285 19334076
- Franich NR Fitzsimons HL Fong DM Klugmann M During MJ Young D 2008 AAV vector-mediated RNAi of mutant huntingtin expression is neuroprotective in a novel genetic rat model of Huntington’s disease Mol Ther 16 947 956 18388917 PMC3793641
- Gagnon KT Pendergraff HM Deleavey GF Swayze EE Potier P Randolph J Roesch EB Chattopadhyaya J Damha MJ Bennett CF 2010 Allele-Selective Inhibition of Mutant Huntingtin Expression with Antisense Oligonucleotides Targeting the Expanded CAG Repeat Biochemistry PMC2991413 21028906
- Gauthier LR Charrin BC Borrell-Pages M Dompierre JP Rangone H Cordelieres FP De Mey J MacDonald ME Lessmann V Humbert S Saudou F 2004 Huntingtin controls neurotrophic support and survival of neurons by enhancing BDNF vesicular transport along microtubules Cell 118 127 138 15242649
- Gray M Shirasaki DI Cepeda C Andre VM Wilburn B Lu XH Tao J Yamazaki I Li SH Sun YE 2008 Full-length human mutant huntingtin with a stable polyglutamine repeat can elicit progressive and selective neuropathogenesis in BACHD mice J Neurosci 28 6182 6195 18550760 PMC2630800
- Gu X Andre VM Cepeda C Li SH Li XJ Levine MS Yang XW 2007 Pathological cell-cell interactions are necessary for striatal pathogenesis in a conditional mouse model of Huntington’s disease Mol Neurodegener 2 8 17470275 PMC1885431
- Harper SQ Staber PD He X Eliason SL Martins IH Mao Q Yang L Kotin RM Paulson HL Davidson BL 2005 RNA interference improves motor and neuropathological abnormalities in a Huntington’s disease mouse model Proc Natl Acad Sci U S A 102 5820 5825 15811941 PMC556303
- Henry SP Geary RS Yu R Levin AA 2001 Drug properties of second-generation antisense oligonucleotides: how do they measure up to their predecessors? Curr Opin Investig Drugs 2 1444 1449 11890363
- Hodgson JG Agopyan N Gutekunst CA Leavitt BR LePiane F Singaraja R Smith DJ Bissada N McCutcheon K Nasir J 1999 A YAC mouse model for Huntington’s disease with full-length mutant huntingtin, cytoplasmic toxicity, and selective striatal neurodegeneration Neuron 23 181 192 10402204
- Hoogeveen AT Willemsen R Meyer N de Rooij KE Roos RA van Ommen GJ Galjaard H 1993 Characterization and localization of the Huntington disease gene product Hum Mol Genet 2 2069 2073 8111375
- Hu J Matsui M Gagnon KT Schwartz JC Gabillet S Arar K Wu J Bezprozvanny I Corey DR 2009 Allele-specific silencing of mutant huntingtin and ataxin-3 genes by targeting expanded CAG repeats in mRNAs Nat Biotechnol 27 478 484 19412185 PMC2765218
- Liu W Kennington LA Rosas HD Hersch S Cha JH Zamore PD Aronin N 2008 Linking SNPs to CAG repeat length in Huntington’s disease patients Nat Methods 5 951 953 18931668 PMC2587014
- Machida Y Okada T Kurosawa M Oyama F Ozawa K Nukina N 2006 rAAV-mediated shRNA ameliorated neuropathology in Huntington disease model mouse Biochem Biophys Res Commun 343 190 197 16530728
- Mangiarini L Sathasivam K Seller M Cozens B Harper A Hetherington C Lawton M Trottier Y Lehrach H Davies SW Bates GP 1996 Exon 1 of the HD gene with an expanded CAG repeat is sufficient to cause a progressive neurological phenotype in transgenic mice Cell 87 493 506 8898202
- McBride JL Boudreau RL Harper SQ Staber PD Monteys AM Martins I Gilmore BL Burstein H Peluso RW Polisky B 2008 Artificial miRNAs mitigate shRNA-mediated toxicity in the brain: implications for the therapeutic development of RNAi Proc Natl Acad Sci U S A 105 5868 5873 18398004 PMC2311380
- McBride JL Pitzer MR Boudreau RL Dufour B Hobbs T Ojeda SR Davidson BL 2011 Preclinical safety of RNAi-mediated HTT suppression in the rhesus macaque as a potential therapy for Huntington’s disease Mol Ther 19 2152 2162 22031240 PMC3242667
- McKay RA Miraglia LJ Cummins LL Owens SR Sasmor H Dean NM 1999 Characterization of a potent and specific class of antisense oligonucleotide inhibitor of human protein kinase C-alpha expression J Biol Chem 274 1715 1722 9880552
- Melone MA Jori FP Peluso G 2005 Huntington’s disease: new frontiers for molecular and cell therapy Curr Drug Targets 6 43 56 15720212
- Nasir J Floresco SB O’Kusky JR Diewert VM Richman JM Zeisler J Borowski A Marth JD Phillips AG Hayden MR 1995 Targeted disruption of the Huntington’s disease gene results in embryonic lethality and behavioral and morphological changes in heterozygotes Cell 81 811 823 7774020
- Peters-Libeu C Miller J Rutenber E Newhouse Y Krishnan P Cheung K Hatters D Brooks E Widjaja K Tran T 2012 Disease-Associated Polyglutamine Stretches in Monomeric Huntingtin Adopt a Compact Structure J Mol Biol PMC3358578 22306738
- Pfister EL Kennington L Straubhaar J Wagh S Liu W DiFiglia M Landwehrmeyer B Vonsattel JP Zamore PD Aronin N 2009 Five siRNAs targeting three SNPs may provide therapy for three-quarters of Huntington’s disease patients Curr Biol 19 774 778 19361997 PMC2746439
- Rodriguez-Lebron E Denovan-Wright EM Nash K Lewin AS Mandel RJ 2005 Intrastriatal rAAV-mediated delivery of anti-huntingtin shRNAs induces partial reversal of disease progression in R6/1 Huntington’s disease transgenic mice Mol Ther 12 618 633 16019264 PMC2656966
- Rosas HD Liu AK Hersch S Glessner M Ferrante RJ Salat DH van der Kouwe A Jenkins BG Dale AM Fischl B 2002 Regional and progressive thinning of the cortical ribbon in Huntington’s disease Neurology 58 695 701 11889230
- Rosas HD Salat DH Lee SY Zaleta AK Pappu V Fischl B Greve D Hevelone N Hersch SM 2008 Cerebral cortex and the clinical expression of Huntington’s disease: complexity and heterogeneity Brain 131 1057 1068 18337273 PMC2657201
- Rosas HD Tuch DS Hevelone ND Zaleta AK Vangel M Hersch SM Salat DH 2006 Diffusion tensor imaging in presymptomatic and early Huntington’s disease: Selective white matter pathology and its relationship to clinical measures Mov Disord 21 1317 1325 16755582
- Smith RA Miller TM Yamanaka K Monia BP Condon TP Hung G Lobsiger CS Ward CM McAlonis-Downes M Wei H 2006 Antisense oligonucleotide therapy for neurodegenerative disease J Clin Invest 116 2290 2296 16878173 PMC1518790
- Van Raamsdonk JM Gibson WT Pearson J Murphy Z Lu G Leavitt BR Hayden MR 2006 Body weight is modulated by levels of full-length huntingtin Hum Mol Genet 15 1513 1523 16571604
- Wang YL Liu W Wada E Murata M Wada K Kanazawa I 2005 Clinico-pathological rescue of a model mouse of Huntington’s disease by siRNA Neurosci Res 53 241 249 16095740
- White JK Auerbach W Duyao MP Vonsattel JP Gusella JF Joyner AL MacDonald ME 1997 Huntingtin is required for neurogenesis and is not impaired by the Huntington’s disease CAG expansion Nat Genet 17 404 410 9398841
- Winer J Jung CK Shackel I Williams PM 1999 Development and validation of real-time quantitative reverse transcriptase-polymerase chain reaction for monitoring gene expression in cardiac myocytes in vitro Anal Biochem 270 41 49 10328763
- Yamamoto A Lucas JJ Hen R 2000 Reversal of neuropathology and motor dysfunction in a conditional model of Huntington’s disease Cell 101 57 66 10778856
- Yu RZ Geary RS Monteith DK Matson J Truong L Fitchett J Levin AA 2004 Tissue disposition of 2′-O-(2-methoxy) ethyl modified antisense oligonucleotides in monkeys J Pharm Sci 93 48 59 14648635
- Yu RZ Zhang H Geary RS Graham M Masarjian L Lemonidis K Crooke R Dean NM Levin AA 2001 Pharmacokinetics and pharmacodynamics of an antisense phosphorothioate oligonucleotide targeting Fas mRNA in mice J Pharmacol Exp Ther 296 388 395 11160622
- Zeitlin S Liu JP Chapman DL Papaioannou VE Efstratiadis A 1995 Increased apoptosis and early embryonic lethality in mice nullizygous for the Huntington’s disease gene homologue Nat Genet 11 155 163 7550343
- Zuccato C Tartari M Crotti A Goffredo D Valenza M Conti L Cataudella T Leavitt BR Hayden MR Timmusk T 2003 Huntingtin interacts with REST/NRSF to modulate the transcription of NRSE-controlled neuronal genes Nat Genet 35 76 83 12881722
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Takeuchi, T., & Nagai, Y. (2017) · Brain Sciences · doi:10.3390/brainsci7100128 · Cited by 71 · see citing works
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Caron, N. S., Banos, R., Yanick, C., Aly, A. E., Byrne, L. M., Smith, E. D., Xie, Y., Smith, S. E. P., Potluri, N., Findlay Black, H., et al. (2021) · The Journal of Neuroscience · doi:10.1523/jneurosci.1865-20.2020 · Cited by 66 · see citing works
Newcombe, E. A., Ruff, K. M., Sethi, A., Ormsby, A. R., Ramdzan, Y. M., Fox, A., Purcell, A. W., Gooley, P. R., Pappu, R. V., & Hatters, D. M. (2018) · Journal of Molecular Biology · doi:10.1016/j.jmb.2018.03.031 · Cited by 66 · see citing works
Therapeutically viable generation of neurons with antisense oligonucleotide suppression of PTB
Maimon, R., Chillon-Marinas, C., Snethlage, C. E., Singhal, S. M., McAlonis-Downes, M., Ling, K., Rigo, F., Bennett, C. F., Da Cruz, S., Hnasko, T. S., et al. (2021) · Nature Neuroscience · doi:10.1038/s41593-021-00864-y · Cited by 62 · see citing works
Self-citationApplication of Novel Degraders Employing Autophagy for Expediting Medicinal Research
Li, X., Liu, Q., Xie, X., Peng, C., Pang, Q., Liu, B., & Han, B. (2023) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.2c01712 · Cited by 46 · see citing works
Petkau, T. L., Hill, A., Connolly, C., Lu, G., Wagner, P., Kosior, N., Blanco, J., & Leavitt, B. R. (2019) · Human Molecular Genetics · doi:10.1093/hmg/ddz009 · Cited by 37 · see citing works
Ferguson, C. M., Godinho, B. M. D. C., Alterman, J. F., Coles, A. H., Hassler, M., Echeverria, D., Gilbert, J. W., Knox, E. G., Caiazzi, J., Haraszti, R. A., et al. (2021) · JCI Insight · doi:10.1172/jci.insight.152203 · Cited by 27 · see citing works
Tejwani, L., Jung, Y., Kokubu, H., Sowmithra, S., Ni, L., Lee, C., Sanders, B., Lee, P. J., Xiang, Y., Luttik, K., et al. (2023) · Journal of Clinical Investigation · doi:10.1172/jci138207 · Cited by 17 · see citing works
“been the disease-causing protein itself (33, 42-45).”
Stanek, L. M., Bu, J., & Shihabuddin, L. S. (2019) · Neurobiology of Disease · doi:10.1016/j.nbd.2019.04.015 · Cited by 15 · see citing works
Self-citationSorets, A. G., Schwensen, K. R., Francini, N., Kjar, A., Abdulrahman, A. M., Shostak, A., Katdare, K. A., Schoch, K. M., Cowell, R. P., Park, J. C., et al. (2025) · Nucleic Acids Research · doi:10.1093/nar/gkaf600 · Cited by 6 · see citing works
“While effective in regions proximal to the lumbar injection site, numerous studies suggest that ASOs are not well suited for deep brain structure targets [ 16 , 47 , 52 ].”
Sorets, A., Schwensen, K., Francini, N., Kjar, A., Abdulrahman, A., Shostak, A., Katdare, K., Schoch, K., Cowell, R., Park, J., et al. (2024) · doi:10.1101/2024.06.09.598079 · Cited by 4 · see citing works
- Authors
- Kordasiewicz, H. B., Stanek, L. M., Wancewicz, E. V., Mazur, C., McAlonis, M. M., Pytel, K. A., Artates, J. W., Weiss, A., Cheng, S. H., Shihabuddin, L. S., Hung, G., Bennett, C. F., & Cleveland, D. W.
- Affiliations
- University of California San Diego (US)
- Ionis Pharmaceuticals (United States) (US)
- Novartis (Switzerland) (CH)
- Corresponding author
- Cleveland, Don W.
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2012-06
- Volume
- 74
- Issue
- 6
- Pages
- 1031-1044
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC3383626
- OpenAlex
- W1997188614
- Cited by
- 770
- References
- 2
- Citations by year
- 2026: 24 · 2025: 42 · 2024: 58 · 2023: 38 · 2022: 59 · 2021: 66 · 2020: 50 · 2019: 71 · 2018: 73 · 2017: 59 · 2016: 54 · 2015: 43 · 2014: 62 · 2013: 46 · 2012: 24
- FWCI
- 23.07
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Neurological Disorders and Stroke (R37NS027036)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Keywords
- Huntington's disease, antisense oligonucleotides, huntingtin, polyglutamine expansion, cerebrospinal fluid infusion, disease reversal, nonhuman primate model, symptomatic treatment
- MeSH terms
- Huntingtin Protein, Animals, Corpus Striatum, Disease Models, Animal, Huntington Disease, Macaca mulatta, Nerve Tissue Proteins, Neurons, Nuclear Proteins, Time, Treatment Outcome, Disease Progression, Oligodeoxyribonucleotides, Antisense, Mice, Infusions, Spinal
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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