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A single-cell map of antisense oligonucleotide activity in the brain

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Mortberg, Meredith A, Gentile, Juliana E, Nadaf, Naeem M, Vanderburg, Charles, Simmons, Sean, Dubinsky, Dan, Slamin, Adam, Maldonado, Salome +6 more·2023·Nucleic Acids Research
DOI 10.1093/nar/gkad371PMC PMC10415122

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Abstract

Antisense oligonucleotides (ASOs) dosed into cerebrospinal fluid (CSF) distribute broadly throughout the central nervous system (CNS). By modulating RNA, they hold the promise of targeting root molecular causes of disease and hold potential to treat myriad CNS disorders. Realization of this potential requires that ASOs must be active in the disease-relevant cells, and ideally, that monitorable biomarkers also reflect ASO activity in these cells. The biodistribution and activity of such centrally delivered ASOs have been deeply characterized in rodent and non-human primate (NHP) models, but usually only in bulk tissue, limiting our understanding of the distribution of ASO activity across individual cells and across diverse CNS cell types. Moreover, in human clinical trials, target engagement is usually monitorable only in a single compartment, CSF. We sought a deeper understanding of how individual cells and cell types contribute to bulk tissue signal in the CNS, and how these are linked to CSF biomarker outcomes. We employed single nucleus transcriptomics on tissue from mice treated with RNase H1 ASOs against Prnp and Malat1 and NHPs treated with an ASO against PRNP. Pharmacologic activity was observed in every cell type, though sometimes with substantial differences in magnitude. Single cell RNA count distributions implied target RNA suppression in every single sequenced cell, rather than intense knockdown in only some cells. Duration of action up to 12 weeks post-dose differed across cell types, being shorter in microglia than in neurons. Suppression in neurons was generally similar to, or more robust than, the bulk tissue. In macaques, PrP in CSF was lowered 40% in conjunction with PRNP knockdown across all cell types including neurons, arguing that a CSF biomarker readout is likely to reflect ASO pharmacodynamic effect in disease-relevant cells in a neuronal disorder. Our results provide a reference dataset for ASO activity distribution in the CNS and establish single nucleus sequencing as a method for evaluating cell type specificity of oligonucleotide therapeutics and other modalities.

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  • Single-nucleus atlases are not suitable for siRNAs, which only degrade cytoplasmic mRNA.

    “While single-nucleus atlases have generated informative datasets for ASOs, this method is not suitable for siRNAs, which only degrade cytoplasmic mRNA [49].”

    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 [49]

    The Introduction and Discussion report that single-nucleus transcriptomics produced informative ASO target-engagement data. The Discussion’s limitations section says the method measured target engagement only in nuclei, but the paper does not establish that it is unsuitable for siRNAs or that siRNAs only degrade cytoplasmic mRNA. Page numbers were not provided in our copy. (LLM, conf=0.86)

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  1. [2]Crooke S.T., Baker B.F., Crooke R.M., Liang X.-H. Antisense technology: an overview and prospectus. Nat. Rev. Drug Discov. 2021; 20: 427– 453. 33762737
  2. [3]Crooke S.T., Wang S., Vickers T.A., Shen W., Liang X.-H. Cellular uptake and trafficking of antisense oligonucleotides. Nat. Biotechnol. 2017; 35: 230– 237. 28244996
  3. [4]Dowdy S.F. Endosomal escape of RNA therapeutics: how do we solve this rate-limiting problem?. RNA. 2023; 29: 396– 401. 36669888 PMC10019367
  4. [5]Liang X.-H., Sun H., Nichols J.G., Crooke S.T. RNase H1-dependent antisense oligonucleotides are robustly active in directing RNA cleavage in both the cytoplasm and the nucleus. Mol. Ther. 2017; 25: 2075– 2092. 28663102 PMC5589097
  5. [6]Corey D.R. Nusinersen, an antisense oligonucleotide drug for spinal muscular atrophy. Nat. Neurosci. 2017; 20: 497– 499. 28192393
  6. [8]Kim J., Hu C., Moufawad El Achkar C., Black L.E., Douville J., Larson A., Pendergast M.K., Goldkind S.F., Lee E.A., Kuniholm A. et al. Patient-customized oligonucleotide therapy for a rare genetic disease. N. Engl. J. Med. 2019; 381: 1644– 1652. 31597037 PMC6961983
  7. [9]Tran H., Moazami M.P., Yang H., McKenna-Yasek D., Douthwright C.L., Pinto C., Metterville J., Shin M., Sanil N., Dooley C. et al. Suppression of mutant C9orf72 expression by a potent mixed backbone antisense oligonucleotide. Nat. Med. 2022; 28: 117– 124. 34949835 PMC8861976
  8. [10]Synofzik M., van Roon-Mom W.M.C., Marckmann G., van Duyvenvoorde H.A., Graessner H., Schüle R., Aartsma-Rus A. Preparing n-of-1 antisense oligonucleotide treatments for rare neurological diseases in Europe: genetic, regulatory, and ethical perspectives. Nucleic Acid Ther. 2022; 32: 83– 94. 34591693 PMC9058873
  9. [11]Korobeynikov V.A., Lyashchenko A.K., Blanco-Redondo B., Jafar-Nejad P., Shneider N.A. Antisense oligonucleotide silencing of FUS expression as a therapeutic approach in amyotrophic lateral sclerosis. Nat. Med. 2022; 28: 104– 116. 35075293 PMC8799464
  10. [12]Wu H., Lima W.F., Zhang H., Fan A., Sun H., Crooke S.T. Determination of the role of the human RNase H1 in the pharmacology of DNA-like antisense drugs. J. Biol. Chem. 2004; 279: 17181– 17189. 14960586
  11. [13]Lima W.F., Rose J.B., Nichols J.G., Wu H., Migawa M.T., Wyrzykiewicz T.K., Siwkowski A.M., Crooke S.T. Human RNase H1 discriminates between subtle variations in the structure of the heteroduplex substrate. Mol. Pharmacol. 2007; 71: 83– 91. 17028158
  12. [14]Lima W.F., Murray H.M., Damle S.S., Hart C.E., Hung G., De Hoyos C.L., Liang X.-H., Crooke S.T. Viable RNaseH1 knockout mice show RNaseH1 is essential for R loop processing, mitochondrial and liver function. Nucleic Acids Res. 2016; 44: 5299– 5312. 27131367 PMC4914116
  13. [15]Khvorova A., Watts J.K. The chemical evolution of oligonucleotide therapies of clinical utility. Nat. Biotechnol. 2017; 35: 238– 248. 28244990 PMC5517098
  14. [19]Tabrizi S.J., Leavitt B.R., Landwehrmeyer G.B., Wild E.J., Saft C., Barker R.A., Blair N.F., Craufurd D., Priller J., Rickards H. et al. Targeting Huntingtin expression in patients with Huntington's disease. N. Engl. J. Med. 2019; 380: 2307– 2316. 31059641
  15. [20]Mazur C., Powers B., Zasadny K., Sullivan J.M., Dimant H., Kamme F., Hesterman J., Matson J., Oestergaard M., Seaman M. et al. Brain pharmacology of intrathecal antisense oligonucleotides revealed through multimodal imaging. JCI Insight. 2019; 4: e129240. 31619586 PMC6824309
  16. [22]Finkel R.S., Chiriboga C.A., Vajsar J., Day J.W., Montes J., De Vivo D.C., Yamashita M., Rigo F., Hung G., Schneider E. et al. Treatment of infantile-onset spinal muscular atrophy with nusinersen: a phase 2, open-label, dose-escalation study. Lancet. 2016; 388: 3017– 3026. 27939059
  17. [23]Hagemann T.L., Powers B., Lin N.-H., Mohamed A.F., Dague K.L., Hannah S.C., Bachmann G., Mazur C., Rigo F., Olsen A.L. et al. Antisense therapy in a rat model of Alexander disease reverses GFAP pathology, white matter deficits, and motor impairment. Sci. Transl. Med. 2021; 13: eabg4711. 34788075 PMC8730534
  18. [25]Zhao H.T., John N., Delic V., Ikeda-Lee K., Kim A., Weihofen A., Swayze E.E., Kordasiewicz H.B., West A.B., Volpicelli-Daley L.A. LRRK2 Antisense Oligonucleotides Ameliorate α-Synuclein Inclusion Formation in a Parkinson's Disease Mouse Model. Mol Ther Nucleic Acids. 2017; 8: 508– 519. 28918051 PMC5573879
  19. [26]Schoch K.M., Ezerskiy L.A., Morhaus M.M., Bannon R.N., Sauerbeck A.D., Shabsovich M., Jafar-Nejad P., Rigo F., Miller T.M. Acute Trem2 reduction triggers increased microglial phagocytosis, slowing amyloid deposition in mice. Proc. Natl. Acad. Sci. U.S.A. 2021; 118: e2100356118. 34187891 PMC8271763
  20. [27]Friedrich J., Kordasiewicz H.B., O’Callaghan B., Handler H.P., Wagener C., Duvick L., Swayze E.E., Rainwater O., Hofstra B., Benneyworth M. et al. Antisense oligonucleotide-mediated ataxin-1 reduction prolongs survival in SCA1 mice and reveals disease-associated transcriptome profiles. JCI Insight. 2018; 3: e123193. 30385727 PMC6238731
  21. [28]Elitt M.S., Barbar L., Shick H.E., Powers B.E., Maeno-Hikichi Y., Madhavan M., Allan K.C., Nawash B.S., Gevorgyan A.S., Hung S. et al. Suppression of proteolipid protein rescues Pelizaeus-Merzbacher disease. Nature. 2020; 585: 397– 403. 32610343 PMC7810164
  22. [29]Cole T.A., Zhao H., Collier T.J., Sandoval I., Sortwell C.E., Steece-Collier K., Daley B.F., Booms A., Lipton J., Welch M. et al. α-Synuclein antisense oligonucleotides as a disease-modifying therapy for Parkinson's disease. JCI Insight. 2021; 6: e135633. 33682798 PMC8021121
  23. [30]Prakash T.P., Graham M.J., Yu J., Carty R., Low A., Chappell A., Schmidt K., Zhao C., Aghajan M., Murray H.F. et al. Targeted delivery of antisense oligonucleotides to hepatocytes using triantennary N-acetyl galactosamine improves potency 10-fold in mice. Nucleic Acids Res. 2014; 42: 8796– 8807. 24992960 PMC4117763
  24. [31]Shin M., Chan I.L., Cao Y., Gruntman A.M., Lee J., Sousa J., Rodríguez T.C., Echeverria D., Devi G., Debacker A.J. et al. Intratracheally administered LNA gapmer antisense oligonucleotides induce robust gene silencing in mouse lung fibroblasts. Nucleic Acids Res. 2022; 50: 8418– 8430. 35920332 PMC9410908
  25. [32]Minikel E.V., Zhao H.T., Le J., O’Moore J., Pitstick R., Graffam S., Carlson G.A., Kavanaugh M.P., Kriz J., Kim J.B. et al. Prion protein lowering is a disease-modifying therapy across prion disease stages, strains and endpoints. Nucleic Acids Res. 2020; 48: 10615– 10631. 32776089 PMC7641729
  26. [34]Biancalani T., Scalia G., Buffoni L., Avasthi R., Lu Z., Sanger A., Tokcan N., Vanderburg C.R., Segerstolpe Å., Zhang M. et al. Deep learning and alignment of spatially resolved single-cell transcriptomes with Tangram. Nat. Methods. 2021; 18: 1352– 1362. 34711971 PMC8566243
  27. [35]Vallabh S.M., Nobuhara C.K., Llorens F., Zerr I., Parchi P., Capellari S., Kuhn E., Klickstein J., Safar J.G., Nery F.C. et al. Prion protein quantification in human cerebrospinal fluid as a tool for prion disease drug development. Proc. Natl. Acad. Sci. U.S.A. 2019; 116: 7793– 7798. 30936307 PMC6475435
  28. [36]Kozareva V., Martin C., Osorno T., Rudolph S., Guo C., Vanderburg C., Nadaf N., Regev A., Regehr W.G., Macosko E. A transcriptomic atlas of mouse cerebellar cortex comprehensively defines cell types. Nature. 2021; 598: 214– 219. 34616064 PMC8494635
  29. [38]Kamath T., Abdulraouf A., Burris S.J., Langlieb J., Gazestani V., Nadaf N.M., Balderrama K., Vanderburg C., Macosko E.Z. Single-cell genomic profiling of human dopamine neurons identifies a population that selectively degenerates in Parkinson's disease. Nat. Neurosci. 2022; 25: 588– 595. 35513515 PMC9076534
  30. [40]Li B., Gould J., Yang Y., Sarkizova S., Tabaka M., Ashenberg O., Rosen Y., Slyper M., Kowalczyk M.S., Villani A.-C. et al. Cumulus provides cloud-based data analysis for large-scale single-cell and single-nucleus RNA-seq. Nat. Methods. 2020; 17: 793– 798. 32719530 PMC7437817
  31. [41]Zheng G.X.Y., Terry J.M., Belgrader P., Ryvkin P., Bent Z.W., Wilson R., Ziraldo S.B., Wheeler T.D., McDermott G.P., Zhu J. et al. Massively parallel digital transcriptional profiling of single cells. Nat. Commun. 2017; 8: 14049. 28091601 PMC5241818
  32. [42]McInnes L., Healy J., Melville J. UMAP: uniform manifold approximation and projection for dimension reduction. 2018; arXiv doi: 18 September 2020, preprint: not peer reviewed https://arxiv.org/abs/1802.03426. · arXiv
  33. [43]Zeisel A., Muñoz-Manchado A.B., Codeluppi S., Lönnerberg P., La Manno G., Juréus A., Marques S., Munguba H., He L., Betsholtz C. et al. Brain structure. Cell types in the mouse cortex and hippocampus revealed by single-cell RNA-seq. Science. 2015; 347: 1138– 1142. 25700174
  34. [44]Li Y., Lopez-Huerta V.G., Adiconis X., Levandowski K., Choi S., Simmons S.K., Arias-Garcia M.A., Guo B., Yao A.Y., Blosser T.R. et al. Distinct subnetworks of the thalamic reticular nucleus. Nature. 2020; 583: 819– 824. 32699411 PMC7394718
  35. [45]Han L., Wei X., Liu C., Volpe G., Zhuang Z., Zou X., Wang Z., Pan T., Yuan Y., Zhang X. et al. Cell transcriptomic atlas of the non-human primate Macaca fascicularis. Nature. 2022; 604: 723– 731. 35418686
  36. [47]Mickelsen L.E., Flynn W.F., Springer K., Wilson L., Beltrami E.J., Bolisetty M., Robson P., Jackson A.C. Cellular taxonomy and spatial organization of the murine ventral posterior hypothalamus. Elife. 2020; 9: e58901. 33119507 PMC7595735
  37. [49]Chen A., Sun Y., Lei Y., Li C., Liao S., Liang Z., Lin F., Yuan N., Li M., Wang K. et al. Global spatial transcriptome of Macaque brain at single-cell resolution. 2022; bioRxiv doi: 23 March 2022, preprint: not peer reviewed 10.1101/2022.03.23.485448. · DOI
  38. [50]Hao Y., Hao S., Andersen-Nissen E., Mauck W.M., Zheng S., Butler A., Lee M.J., Wilk A.J., Darby C., Zager M. et al. Integrated analysis of multimodal single-cell data. Cell. 2021; 184: 3573– 3587. 34062119 PMC8238499
  39. [51]Yu R.Z., Graham M.J., Post N., Riney S., Zanardi T., Hall S., Burkey J., Shemesh C.S., Prakash T.P., Seth P.P. et al. Disposition and pharmacology of a GalNAc3-conjugated ASO targeting human lipoprotein(a) in mice. Mol. Ther. Nucleic Acids. 2016; 5: e317. 27138177 PMC5014512
  40. [52]Raymond G.J., Zhao H.T., Race B., Raymond L.D., Williams K., Swayze E.E., Graffam S., Le J., Caron T., Stathopoulos J. et al. Antisense oligonucleotides extend survival of prion-infected mice. JCI Insight. 2019; 5: e131175. 31361599 PMC6777807
  41. [54]Ding J., Adiconis X., Simmons S.K., Kowalczyk M.S., Hession C.C., Marjanovic N.D., Hughes T.K., Wadsworth M.H., Burks T., Nguyen L.T. et al. Systematic comparison of single-cell and single-nucleus RNA-sequencing methods. Nat. Biotechnol. 2020; 38: 737– 746. 32341560 PMC7289686
  42. [55]Sarkar A., Stephens M. Separating measurement and expression models clarifies confusion in single-cell RNA sequencing analysis. Nat. Genet. 2021; 53: 770– 777. 34031584 PMC8370014
  43. [56]Mortberg M.A., Zhao H.T., Reidenbach A.G., Gentile J.E., Kuhn E., O’Moore J., Dooley P.M., Connors T.R., Mazur C., Allen S.W. et al. Regional variability and genotypic and pharmacodynamic effects on PrP concentration in the CNS. JCI Insight. 2022; 7: e156532. 35133987 PMC8986079
  44. [57]Bernard D., Prasanth K.V., Tripathi V., Colasse S., Nakamura T., Xuan Z., Zhang M.Q., Sedel F., Jourdren L., Coulpier F. et al. A long nuclear-retained non-coding RNA regulates synaptogenesis by modulating gene expression. EMBO J. 2010; 29: 3082– 3093. 20729808 PMC2944070
  45. [58]Bennett C.F., Baker B.F., Pham N., Swayze E., Geary R.S. Pharmacology of Antisense Drugs. Annu. Rev. Pharmacol. Toxicol. 2017; 57: 81– 105. 27732800
  46. [59]Anderson B.A., Freestone G.C., Low A., De-Hoyos C.L., Iii W.J.D., Østergaard M.E., Migawa M.T., Fazio M., Wan W.B., Berdeja A. et al. Towards next generation antisense oligonucleotides: mesylphosphoramidate modification improves therapeutic index and duration of effect of gapmer antisense oligonucleotides. Nucleic Acids Res. 2021; 49: 9026– 9041. 34417625 PMC8450106
  47. [60]Seth P.P., Vasquez G., Allerson C.A., Berdeja A., Gaus H., Kinberger G.A., Prakash T.P., Migawa M.T., Bhat B., Swayze E.E. Synthesis and biophysical evaluation of 2’,4’-constrained 2’O-methoxyethyl and 2’,4’-constrained 2’O-ethyl nucleic acid analogues. J. Org. Chem. 2010; 75: 1569– 1581. 20136157
  48. [61]Brautigam H., Steele J.W., Westaway D., Fraser P.E., St George-Hyslop P.H., Gandy S., Hof P.R., Dickstein D.L. The isotropic fractionator provides evidence for differential loss of hippocampal neurons in two mouse models of Alzheimer's disease. Mol Neurodegener. 2012; 7: 58. 23173713 PMC3551697
  49. [62]Herculano-Houzel S., Messeder D.J., Fonseca-Azevedo K., Pantoja N.A. When larger brains do not have more neurons: increased numbers of cells are compensated by decreased average cell size across mouse individuals. Front. Neuroanat. 2015; 9: 64. 26082686 PMC4450177
  50. [63]Chan K.Y., Jang M.J., Yoo B.B., Greenbaum A., Ravi N., Wu W.-L., Sánchez-Guardado L., Lois C., Mazmanian S.K., Deverman B.E. et al. Engineered AAVs for efficient noninvasive gene delivery to the central and peripheral nervous systems. Nat. Neurosci. 2017; 20: 1172– 1179. 28671695 PMC5529245
  51. [64]Füger P., Hefendehl J.K., Veeraraghavalu K., Wendeln A.-C., Schlosser C., Obermüller U., Wegenast-Braun B.M., Neher J.J., Martus P., Kohsaka S. et al. Microglia turnover with aging and in an Alzheimer's model via long-term in vivo single-cell imaging. Nat. Neurosci. 2017; 20: 1371– 1376. 28846081
  52. [65]Wälchli T., Bisschop J., Carmeliet P., Zadeh G., Monnier P.P., De Bock K., Radovanovic I. Shaping the brain vasculature in development and disease in the single-cell era. Nat. Rev. Neurosci. 2023; 24: 271– 298. 36941369 PMC10026800
  53. [66]Hariharan V.N., Shin M., Chang C.-W., O’Reilly D., Biscans A., Yamada K., Guo Z., Somasundaran M., Tang Q., Monopoli K. et al. Divalent siRNAs are bioavailable in the lung and efficiently block SARS-CoV-2 infection. Proc. Natl. Acad. Sci. U.S.A. 2023; 120: e2219523120. 36893269 PMC10089225
  54. [67]GTEx Consortium The GTEx Consortium atlas of genetic regulatory effects across human tissues. Science. 2020; 369: 1318– 1330. 32913098 PMC7737656
  55. [68]Mortberg M.A., Vallabh S.M., Minikel E.V. Disease stages and therapeutic hypotheses in two decades of neurodegenerative disease clinical trials. Sci. Rep. 2022; 12: 17708. 36271285 PMC9587287
  56. [70]Minikel E.V., Vallabh S.M., Orseth M.C., Brandel J.-P., Haïk S., Laplanche J.-L., Zerr I., Parchi P., Capellari S., Safar J. et al. Age at onset in genetic prion disease and the design of preventive clinical trials. Neurology. 2019; 93: e125– e134. 31171647 PMC6656649
  57. [71]Prusiner S.B. Prions. Proc. Natl. Acad. Sci. U.S.A. 1998; 95: 13363– 13383. 9811807 PMC33918
  58. [72]Vallabh S.M., Minikel E.V., Schreiber S.L., Lander E.S. Towards a treatment for genetic prion disease: trials and biomarkers. Lancet Neurol. 2020; 19: 361– 368. 32199098
  59. [73]Mortberg M.A., Minikel E.V., Vallabh S.M. Analysis of non-human primate models for evaluating prion disease therapeutic efficacy. PLoS Pathog. 2022; 18: e1010728. 35994510 PMC9436048
  60. [74]Krejciova Z., Alibhai J., Zhao C., Krencik R., Rzechorzek N.M., Ullian E.M., Manson J., Ironside J.W., Head M.W., Chandran S. Human stem cell-derived astrocytes replicate human prions in a PRNP genotype-dependent manner. J. Exp. Med. 2017; 214: 3481– 3495. 29141869 PMC5716027
  61. [75]Aguzzi A., Liu Y. A role for astroglia in prion diseases. J. Exp. Med. 2017; 214: 3477– 3479. 29162644 PMC5716049
  62. [76]Lakkaraju A.K.K., Sorce S., Senatore A., Nuvolone M., Guo J., Schwarz P., Moos R., Pelczar P., Aguzzi A. Glial activation in prion diseases is selectively triggered by neuronal PrPSc. Brain Pathol. 2022; 32: e13056. 35178783 PMC9425016
  63. [77]Brandner S., Isenmann S., Raeber A., Fischer M., Sailer A., Kobayashi Y., Marino S., Weissmann C., Aguzzi A. Normal host prion protein necessary for scrapie-induced neurotoxicity. Nature. 1996; 379: 339– 343. 8552188
  64. [78]Mallucci G., Dickinson A., Linehan J., Klöhn P.-C., Brandner S., Collinge J. Depleting neuronal PrP in prion infection prevents disease and reverses spongiosis. Science. 2003; 302: 871– 874. 14593181
  65. [79]Hwang D., Lee I.Y., Yoo H., Gehlenborg N., Cho J.-H., Petritis B., Baxter D., Pitstick R., Young R., Spicer D. et al. A systems approach to prion disease. Mol. Syst. Biol. 2009; 5: 252. 19308092 PMC2671916
  66. [80]Herbst A., Ness A., Johnson C.J., McKenzie D., Aiken J.M. Transcriptomic responses to prion disease in rats. BMC Genomics (Electronic Resource). 2015; 16: 682. PMC4560926 26341492
  67. [81]Sorce S., Nuvolone M., Russo G., Chincisan A., Heinzer D., Avar M., Pfammatter M., Schwarz P., Delic M., Müller M. et al. Genome-wide transcriptomics identifies an early preclinical signature of prion infection. PLoS Pathog. 2020; 16: e1008653. 32598380 PMC7360066
  68. [82]Slota J.A., Sajesh B.V., Frost K.F., Medina S.J., Booth S.A. Dysregulation of neuroprotective astrocytes, a spectrum of microglial activation states, and altered hippocampal neurogenesis are revealed by single-cell RNA sequencing in prion disease. Acta Neuropathol. Commun. 2022; 10: 161. 36352465 PMC9647949
  69. [83]Dimitriadis A., Zhang F., Murphy T., Trainer T., Jaunmuktane Z., Schmidt C., Nazari T., Linehan J., Brandner S., Collinge J. et al. Single-nuclei transcriptomics of mammalian prion diseases identifies dynamic gene signatures shared between species. 2022; bioRxiv doi: 15 September 2022, preprint: not peer reviewed 10.1101/2022.09.13.507650. · DOI
  70. [84]Nazor Friberg K., Hung G., Wancewicz E., Giles K., Black C., Freier S., Bennett F., Dearmond S.J., Freyman Y., Lessard P. et al. Intracerebral infusion of antisense oligonucleotides into prion-infected mice. Mol. Ther. Nucleic Acids. 2012; 1: e9. 23344724 PMC3381600

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Authors
Mortberg, M. A., Gentile, J. E., Nadaf, N. M., Vanderburg, C., Simmons, S., Dubinsky, D., Slamin, A., Maldonado, S., Petersen, C. L., Jones, N., Kordasiewicz, H. B., Zhao, H. T., Vallabh, S. M., & Minikel, E. V.
Affiliations
  • Broad Institute (US)
  • Ionis Pharmaceuticals (United States) (US)
Corresponding author
  • Vallabh, Sonia M
  • Minikel, Eric Vallabh
ORCID
Venue
Nucleic Acids Research
Publisher
Oxford University Press (OUP)
Published
2023-05-16
Volume
51
Issue
14
Pages
7109-7124
ISSN
  • 0305-1048 (ISSN-L)
  • 1362-4962
DOI
10.1093/nar/gkad371
PMC
PMC10415122
OpenAlex
W4376641156
Cited by
54
References
10
Citations by year
2026: 16 · 2025: 13 · 2024: 20 · 2023: 5
FWCI
4.81
Type
journal article
Language
en
Open access
Licence
Locations
  • Nucleic Acids Research (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion, cc-by)
Funders
  • Ono Pharma Foundation
  • Ionis Pharmaceuticals
  • National Institutes of Health (R21 TR003040, R01 NS125255)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
Keywords
antisense oligonucleotides, cerebrospinal fluid, central nervous system, single-nucleus transcriptomics, cell type specificity, RNase H1, prion protein gene, MALAT1, prion protein, microglia, neurons, pharmacodynamics, cerebrospinal fluid biomarkers, oligonucleotide therapeutics, macaque, mice

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