IP Library › Granted Patent US 12,281,305
Granted Patent B2
US 12,281,305 · App. 17/294,859 · Granted Apr 22, 2025

Compounds and methods for reducing prion expression

Inventors: Susan M. Freier (San Diego, CA); Huynh-Hoa Bui (San Diego, CA); Hien Thuy Zhao (San Diego, CA)
Assignee: Ionis Pharmaceuticals, Inc.
C12N15/113A61K31/7088C12N2310/14C12N2310/31C12N2310/315C12N2310/321C12N2310/322C12N2310/3231C12N2310/3341C12N2310/34C12N2310/341C12N2310/351C12N2320/35
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Quick Facts
Patent No.
US 12,281,305
App. No.
17/294,859
Granted
Apr 22, 2025
Kind
B2
Abstract

Provided are compounds, methods, and pharmaceutical compositions for reducing the amount or activity of PRNP RNA in a cell or animal, and in certain instances reducing the amount of PrP protein in a cell or animal. Such compounds, methods, and pharmaceutical compositions are useful to ameliorate at least one symptom or hallmark of a neurodegenerative disease. Such symptoms and hallmarks spongiform changes in the brain, development of abnormal protein aggregates, neuronal loss, markers of neuronal loss, rapidly progressing dementia, and death. Such neurodegenerative diseases include prion diseases, Creutzfeldt-Jakob disease (CJD), variant Creutzfeldt-Jakob Disease (vCJD), familial Creutzfeldt-Jakob Disease (fCJD), Gerstmann-Straussler-Scheinker syndrome, fatal familial insomnia, kuru, Alzheimer's disease, or Parkinson's disease.

Claims (38)

1. A modified oligonucleotide according to the following chemical structure:

or a salt thereof.

2. The modified oligonucleotide of claim 1 , which is the sodium salt of the potassium salt.

3. A pharmaceutical composition comprising the modified oligonucleotide of claim 1 , and a pharmaceutically acceptable diluent.

4. The pharmaceutical composition of claim 3 , wherein the pharmaceutically acceptable diluent is artificial cerebrospinal fluid.

5. The pharmaceutical composition of claim 4 , wherein the pharmaceutical composition consists essentially of the modified oligonucleotide and artificial cerebrospinal fluid.

6. A population of modified oligonucleotides of claim 1 , wherein all of the phosphorothioate internucleoside linkages of the modified oligonucleotide are stereorandom.

7. A pharmaceutical composition comprising the population of modified oligonucleotides of claim 6 , and a pharmaceutically acceptable diluent.

8. The pharmaceutical composition of claim 7 , wherein the pharmaceutically acceptable diluent is artificial cerebrospinal fluid.

9. The pharmaceutical composition of claim 8 , wherein the pharmaceutical composition consists essentially of the population of modified oligonucleotides and artificial cerebrospinal fluid.

10. A modified oligonucleotide according to the following chemical structure:

11. A pharmaceutical composition comprising the modified oligonucleotide of claim 10 and a pharmaceutically acceptable diluent.

12. The pharmaceutical composition of claim 11 , wherein the pharmaceutically acceptable diluent is artificial cerebrospinal fluid.

13. The pharmaceutical composition of claim 12 , wherein the pharmaceutical composition consists essentially of the modified oligonucleotide and artificial cerebrospinal fluid.

14. A population of modified oligonucleotides of claim 10 , wherein all of the phosphorothioate internucleoside linkages of the modified oligonucleotide are stereorandom.

15. A pharmaceutical composition comprising the population of modified oligonucleotides of claim 14 , and a pharmaceutically acceptable diluent.

16. The pharmaceutical composition of claim 15 , wherein the pharmaceutically acceptable diluent is artificial cerebrospinal fluid.

17. The pharmaceutical composition of claim 16 , wherein the pharmaceutical composition consists essentially of the population of modified oligonucleotides and artificial cerebrospinal fluid.

18. A compound comprising a modified oligonucleotide according to the following chemical notation: Ges Teo Geo Teo m Ceo Aeo Tds Ads Ads Tds Tds Tds Tds m Cds Tds Tds Aeo Ges m Ces Te (SEQ ID NO: 2302), wherein,

A=an adenine nucleobase,

mC=a 5-methylcytosine nucleobase,

G=a guanine nucleobase,

T=a thymine nucleobase,

e=a 2′-MOE modified sugar,

d=a 2′-β-D deoxyribosyl sugar,

s=a phosphorothioate internucleoside linkage, and

o=a phosphodiester internucleoside linkage.

19. A pharmaceutical composition comprising a compound of claim 18 , and a pharmaceutically acceptable diluent.

20. The pharmaceutical composition of claim 19 , wherein the pharmaceutically acceptable diluent is artificial cerebrospinal fluid.

21. The pharmaceutical composition of claim 20 , wherein the pharmaceutical composition consists essentially of the compound and artificial cerebrospinal fluid.

22. The compound of claim 18 , comprising the modified oligonucleotide covalently linked to a conjugate group.

23. A pharmaceutical composition comprising a compound of claim 22 , and a pharmaceutically acceptable diluent.

24. The pharmaceutical composition of claim 23 , wherein the pharmaceutically acceptable diluent is artificial cerebrospinal fluid.

25. The pharmaceutical composition of claim 24 , wherein the pharmaceutical composition consists essentially of the compound and artificial cerebrospinal fluid.

26. A population of compounds of claim 18 , wherein all of the phosphorothioate internucleoside linkages of the compound are stereorandom.

27. A pharmaceutical composition comprising the population of compounds of claim 26 , and a pharmaceutically acceptable diluent.

28. The pharmaceutical composition of claim 27 , wherein the pharmaceutically acceptable diluent is artificial cerebrospinal fluid.

29. The pharmaceutical composition of claim 28 , wherein the pharmaceutical composition consists essentially of the population of compounds and artificial cerebrospinal fluid.

Continuity (2)
Provisional Application 62770386 · Nov 21, 2018
Related Publication 20220025366A1 · Jan 27, 2022
References Cited (256)
US 3687808A · Merigan et al. · 1972 [cited by applicant]
US 4415732A · Caruthers et al. · 1983 [cited by applicant]
US 4469863A · Ts'o et al. · 1984 [cited by applicant]
US 4476301A · Imbach et al. · 1984 [cited by applicant]
US 4500707A · Caruthers et al. · 1985 [cited by applicant]
US 4725677A · Koster et al. · 1988 [cited by applicant]
US 4845205A · Huynh Dinh et al. · 1989 [cited by applicant]
US 4973679A · Caruthers et al. · 1990 [cited by applicant]
US 4981957A · Lebleu et al. · 1991 [cited by applicant]
US 5013830A · Ohutsuka et al. · 1991 [cited by applicant]
US 5023243A · Tullis · 1991 [cited by applicant]
US 5034506A · Summerton et al. · 1991 [cited by applicant]
US 5118800A · Smith et al. · 1992 [cited by applicant]
US 5130302A · Spielvogel et al. · 1992 [cited by applicant]
US 5132418A · Caruthers et al. · 1992 [cited by applicant]
US 5134066A · Rogers et al. · 1992 [cited by applicant]
US RE34036E · McGeehan · 1992 [cited by applicant]
US 5149797A · Pederson et al. · 1992 [cited by applicant]
US 5166315A · Summerton et al. · 1992 [cited by applicant]
US 5175273A · Bischofberger et al. · 1992 [cited by applicant]
US 5177196A · Meyer, Jr. et al. · 1993 [cited by applicant]
US 5177198A · Spielvogel et al. · 1993 [cited by applicant]
US 5188897A · Suhadolnik et al. · 1993 [cited by applicant]
US 5194599A · Froehler et al. · 1993 [cited by applicant]
US 5214134A · Weis et al. · 1993 [cited by applicant]
US 5216141A · Benner · 1993 [cited by applicant]
US 5220007A · Pederson et al. · 1993 [cited by applicant]
US 5223618A · Cook et al. · 1993 [cited by applicant]
US 5235033A · Summerton et al. · 1993 [cited by applicant]
US 5256775A · Froehler · 1993 [cited by applicant]
US 5264423A · Cohen et al. · 1993 [cited by applicant]
US 5264562A · Matteucci · 1993 [cited by applicant]
US 5264564A · Matteucci · 1993 [cited by applicant]
US 5185444A · Summerton et al. · 1993 [cited by applicant]
US 5276019A · Cohen et al. · 1994 [cited by applicant]
US 5286717A · Cohen et al. · 1994 [cited by applicant]
US 5319080A · Leumann · 1994 [cited by applicant]
US 5321131A · Agrawal et al. · 1994 [cited by applicant]
US 5359044A · Cook et al. · 1994 [cited by applicant]
US 5366878A · Pederson et al. · 1994 [cited by applicant]
US 5367066A · Urdea et al. · 1994 [cited by applicant]
US 5378825A · Cook et al. · 1995 [cited by applicant]
US 5386023A · Sanghvi et al. · 1995 [cited by applicant]
US 5393878A · Leumann · 1995 [cited by applicant]
US 5399676A · Froehler · 1995 [cited by applicant]
US 5403711A · Walder et al. · 1995 [cited by applicant]
US 5405938A · Sumerton et al. · 1995 [cited by applicant]
US 5405939A · Suhadolnik et al. · 1995 [cited by applicant]
US 5432272A · Benner · 1995 [cited by applicant]
US 5434257A · Matteucci · 1995 [cited by applicant]
US 5446137A · Maag et al. · 1995 [cited by applicant]
US 5453496A · Caruthers et al. · 1995 [cited by applicant]
US 5455233A · Spielvogel et al. · 1995 [cited by applicant]
US 5457187A · Gmelner et al. · 1995 [cited by applicant]
US 5457191A · Cook et al. · 1995 [cited by applicant]
US 5459255A · Cook et al. · 1995 [cited by applicant]
US 5466677A · Baxter et al. · 1995 [cited by applicant]
US 5466786A · Burh et al. · 1995 [cited by applicant]
US 5470967A · Huie et al. · 1995 [cited by applicant]
US 5476925A · Letsinger et al. · 1995 [cited by applicant]
US 5484908A · Froehler et al. · 1996 [cited by applicant]
US 5489677A · Sanghvi et al. · 1996 [cited by applicant]
US 5491133A · Walder et al. · 1996 [cited by applicant]
US 5502177A · Matteucci et al. · 1996 [cited by applicant]
US 5508270A · Baxter et al. · 1996 [cited by applicant]
US 5514785A · Van Ness et al. · 1996 [cited by applicant]
US 5519126A · Hecht · 1996 [cited by applicant]
US 5519134A · Acevedo et al. · 1996 [cited by applicant]
US 5525711A · Hawkins et al. · 1996 [cited by applicant]
US 5527899A · Froehler · 1996 [cited by applicant]
US 5536821A · Agrawal et al. · 1996 [cited by applicant]
US 5541306A · Agrawal et al. · 1996 [cited by applicant]
US 5541307A · Cook et al. · 1996 [cited by applicant]
US 5550111A · Suhadolnik et al. · 1996 [cited by applicant]
US 5552540A · Haralambidis · 1996 [cited by applicant]
US 5561225A · Maddry et al. · 1996 [cited by applicant]
US 5563253A · Agrawal et al. · 1996 [cited by applicant]
US 5565350A · Kmiec · 1996 [cited by applicant]
US 5565555A · Froehler et al. · 1996 [cited by applicant]
US 5567811A · Mistura et al. · 1996 [cited by applicant]
US 5571799A · Tkachuk et al. · 1996 [cited by applicant]
US 5576427A · Cook et al. · 1996 [cited by applicant]
US 5587361A · Cook et al. · 1996 [cited by applicant]
US 5587469A · Cook et al. · 1996 [cited by applicant]
US 5587470A · Cook et al. · 1996 [cited by applicant]
US 5591722A · Montgomery et al. · 1997 [cited by applicant]
US 5594121A · Froehler et al. · 1997 [cited by applicant]
US 5596086A · Matteucci · 1997 [cited by applicant]
US 5596091A · Switzer · 1997 [cited by applicant]
US 5597909A · Urdea et al. · 1997 [cited by applicant]
US 5602240A · De Mesmaeker et al. · 1997 [cited by applicant]
US 5608046A · Cook et al. · 1997 [cited by applicant]
US 5610289A · Cook et al. · 1997 [cited by applicant]
US 5610300A · Altmann et al. · 1997 [cited by applicant]
US 5614617A · Cook et al. · 1997 [cited by applicant]
US 5618704A · Sanghvi et al. · 1997 [cited by applicant]
US 5623065A · Cook et al. · 1997 [cited by applicant]
US 5623070A · Cook et al. · 1997 [cited by applicant]
US 5625050A · Beaton et al. · 1997 [cited by applicant]
US 5627053A · Usman et al. · 1997 [cited by applicant]
US 5633360A · Bishofberger et al. · 1997 [cited by applicant]
US 5639873A · Barascut et al. · 1997 [cited by applicant]
US 5645985A · Froehler et al. · 1997 [cited by applicant]
US 5646265A · McGee · 1997 [cited by applicant]
US 5646269A · Matteucci · 1997 [cited by applicant]
US 5652355A · Metelev et al. · 1997 [cited by applicant]
US 5652356A · Agrawal · 1997 [cited by applicant]
US 5663312A · Chaturvedula · 1997 [cited by applicant]
US 5670633A · Cook et al. · 1997 [cited by applicant]
US 5672697A · Buhr et al. · 1997 [cited by applicant]
US 5677437A · Teng et al. · 1997 [cited by applicant]
US 5677439A · Weis et al. · 1997 [cited by applicant]
US 5681941A · Cook et al. · 1997 [cited by applicant]
US 5698685A · Summerton et al. · 1997 [cited by applicant]
US 5700920A · Altmann et al. · 1997 [cited by applicant]
US 5700922A · Cook · 1997 [cited by applicant]
US 5721218A · Froehler · 1998 [cited by applicant]
US 5750692A · Cook et al. · 1998 [cited by applicant]
US 5763588A · Matteucci et al. · 1998 [cited by applicant]
US 5792608A · Swaminathan et al. · 1998 [cited by applicant]
US 5792847A · Burh et al. · 1998 [cited by applicant]
US 5801154A · Baracchini et al. · 1998 [cited by applicant]
US 5808027A · Cook et al. · 1998 [cited by applicant]
US 5830653A · Froehler et al. · 1998 [cited by applicant]
US 5859221A · Cook et al. · 1999 [cited by applicant]
US 5948903A · Cook et al. · 1999 [cited by applicant]
US 5994517A · Ts'O · 1999 [cited by applicant]
US 6005087A · Cook et al. · 1999 [cited by applicant]
US 6005096A · Matteucci et al. · 1999 [cited by applicant]
US 6166199A · Cook et al. · 2000 [cited by applicant]
US 6300319B1 · Manoharan · 2001 [cited by applicant]
US 6426220B1 · Bennett et al. · 2002 [cited by applicant]
US 6525191B1 · Ramasamy · 2003 [cited by applicant]
US 6531584B1 · Cook et al. · 2003 [cited by applicant]
US 6582908B2 · Fodor et al. · 2003 [cited by applicant]
US 6600032B1 · Manoharan et al. · 2003 [cited by applicant]
US 6660720B2 · Manoharan · 2003 [cited by applicant]
US 6770748B2 · Imanishi et al. · 2004 [cited by applicant]
US 7015315B1 · Cook et al. · 2006 [cited by applicant]
US 7053207B2 · Wengel et al. · 2006 [cited by applicant]
US 7101993B1 · Cook et al. · 2006 [cited by applicant]
US 7250289B2 · Zhou · 2007 [cited by applicant]
US 7262177B2 · Ts'o et al. · 2007 [cited by applicant]
US 7399845B2 · Seth et al. · 2008 [cited by applicant]
US 7427672B2 · Imanishi et al. · 2008 [cited by applicant]
US 7491805B2 · Vargeese et al. · 2009 [cited by applicant]
US 7547684B2 · Seth et al. · 2009 [cited by applicant]
US 7569686B1 · Bhat et al. · 2009 [cited by applicant]
US 7666854B2 · Seth et al. · 2010 [cited by applicant]
US 7696345B2 · Allerson et al. · 2010 [cited by applicant]
US 7723509B2 · Manoharan et al. · 2010 [cited by applicant]
US 7741457B2 · Swayze et al. · 2010 [cited by applicant]
US 7750131B2 · Seth et al. · 2010 [cited by applicant]
US 7875733B2 · Bhat et al. · 2011 [cited by applicant]
US 7939677B2 · Bhat et al. · 2011 [cited by applicant]
US 8022193B2 · Swayze et al. · 2011 [cited by applicant]
US 8030467B2 · Seth et al. · 2011 [cited by applicant]
US 8080644B2 · Wengel et al. · 2011 [cited by applicant]
US 8088746B2 · Seth et al. · 2012 [cited by applicant]
US 8088904B2 · Swayze et al. · 2012 [cited by applicant]
US 8106022B2 · Manoharan et al. · 2012 [cited by applicant]
US 8124745B2 · Allerson et al. · 2012 [cited by applicant]
US 8153365B2 · Wengel et al. · 2012 [cited by applicant]
US 8268980B2 · Seth et al. · 2012 [cited by applicant]
US 8278283B2 · Seth et al. · 2012 [cited by applicant]
US 8278425B2 · Prakash et al. · 2012 [cited by applicant]
US 8278426B2 · Seth et al. · 2012 [cited by applicant]
US 8440803B2 · Swayze et al. · 2013 [cited by applicant]
US 8501805B2 · Seth et al. · 2013 [cited by applicant]
US 8530640B2 · Seth et al. · 2013 [cited by applicant]
US 8546556B2 · Seth et al. · 2013 [cited by applicant]
US RE44779E · Imanishi et al. · 2014 [cited by applicant]
US 8669102B2 · Bennett · 2014 [cited by examiner]
US 8828956B2 · Manoharan et al. · 2014 [cited by applicant]
US 9005906B2 · Swayze et al. · 2015 [cited by applicant]
US 9012421B2 · Migawa et al. · 2015 [cited by applicant]
US 9127276B2 · Prakash et al. · 2015 [cited by applicant]
US 9290760B2 · Rajeev et al. · 2016 [cited by applicant]
US 20010053519A1 · Fodor et al. · 2001 [cited by applicant]
US 20020081645A1 · Collinge · 2002 [cited by applicant]
US 20030158403A1 · Manoharan et al. · 2003 [cited by applicant]
US 20030175906A1 · Manoharan et al. · 2003 [cited by applicant]
US 20030228597A1 · Cowsert et al. · 2003 [cited by applicant]
US 20040014048A1 · Monia et al. · 2004 [cited by applicant]
US 20040171570A1 · Allerson et al. · 2004 [cited by applicant]
US 20050053583A1 · Sakaguchi et al. · 2005 [cited by applicant]
US 20050130923A1 · Bhat et al. · 2005 [cited by applicant]
US 20050255487A1 · Khvorova et al. · 2005 [cited by applicant]
US 20060148740A1 · Platenburg · 2006 [cited by applicant]
US 20060280745A1 · Collinge et al. · 2006 [cited by applicant]
US 20070031844A1 · Khvorova et al. · 2007 [cited by applicant]
US 20070123480A1 · Juteau et al. · 2007 [cited by applicant]
US 20080039618A1 · Allerson et al. · 2008 [cited by applicant]
US 20080085269A1 · Eisenbach-Schwartz · 2008 [cited by applicant]
US 20100190837A1 · Migawa et al. · 2010 [cited by applicant]
US 20100197762A1 · Swayze et al. · 2010 [cited by applicant]
US 20110269818A1 · Bennett et al. · 2011 [cited by applicant]
US 20130130378A1 · Manoharan et al. · 2013 [cited by applicant]
US 20140107330A1 · Freier et al. · 2014 [cited by applicant]
US 20150018540A1 · Prakash et al. · 2015 [cited by applicant]
US 20150184153A1 · Freier et al. · 2015 [cited by applicant]
US 20150191727A1 · Migawa et al. · 2015 [cited by applicant]
US 20150267195A1 · Seth et al. · 2015 [cited by applicant]
US 20150275212A1 · Albaek et al. · 2015 [cited by applicant]
US 20160304871A1 · Rigo · 2016 [cited by examiner]
US 20190381007A1 · Maccecchini · 2019 [cited by applicant]
CN 103255142A · 2013 [cited by applicant]
JP 2007252288A · 2007 [cited by applicant]
WO 2005078093A1 · 2005 [cited by applicant]
WO WO2010019270 · 2010 [cited by applicant]
WO WO2018007980 · 2018 [cited by applicant]
WO WO2020106996 · 2020 [cited by applicant]
WO 2023164696A2 · 2023 [cited by applicant]
NC_000020.11, Start: 4686151, Stop: 4701588, PRNP, NCBI [cited by examiner]
Ostergaard et al., 2020, “Understanding the effect of controlling phosphorothioate chirality in the DNA gap on the potency and safety of gapmer antisense oligonucleotides” Nucleic Acids Research, 2020, 48(4), p. 1691-17… [cited by examiner]
Wan et al., 2014, “Synthesis, biophysical properties and biological activity of second generation antisense oligonucleotides containing chiral phosphorothioate linkages” Nucleic Acids Research, 42(22), p. 13456-13468 (Y… [cited by examiner]
Wozniak and Brezinski, 2023, “Biological Catalysis and Information Storage Have Relied on N-Glycosyl Derivatives of—D-Ribofuranose since the Origins of Life” Biomolecules, 13(5), 782, p. 1-21 (Year: 2023). [cited by examiner]
[cited by examiner]
Minikel et al., Jun. 26, 2020, “Prion protein lowering is a disease-modifying therapy across prion disease stages, strains, and endpoints” bioRxiv, doi: 10.1101/2020.03.27.011940 (Year: 2020). [cited by examiner]
Raymond et al., Jul. 30, 2019, “Antisense oligonucleotides extend survival of prion-infected mice” JCI Insight, 2019;4(16):e131175 (Year: 2019). [cited by examiner]
Barbieri et al., “Silencing of cellular prion protein (PrPC) expression by DNA-antisense oligonucleotides induces autophagy-dependent cell death in glioma cells” Autophagy (2011) 7: 840-853. [cited by applicant]
Branch et al., “A good antisense molecule is hard to find,” TIBS (1998) 23:45-50. [cited by applicant]
Chin “On the Preparation and Utilization of Isolated and Purified Oligonucleotides” Document purportedly located on a CD-ROM and contributed to the public collection of the Katherine R. Everett Law Library of the Univer… [cited by applicant]
Crooke et al., “Basic Principles of Antisense Therapeutics” Antisense Research and Application (1998) Chapter 1:1-50. [cited by applicant]
Crooke, St., et al., “Antisense Drug Technology” Second Edition, CRC Press (2008) Chapters 1-28. [cited by applicant]
Daude et al., “Specific inhibition of pathological prion protein accumulation by small interfering RNAs” Journal of Cell Science (2003) 116(13):2775-2779. [cited by applicant]
Egli, et al., “Synthesis, improved antisense activity and structural rationale for the divergent RNA affinities of 3′-fluoro hexitol nucleic acid (FHNA and Ara-FHNA) modified oligonucleotides.” J Am Chem (2011) 133(41):… [cited by applicant]
Erana et al., “Prion-like disorders and Transmissible Spongiform Encephalopathies: An overview of the mechanistic features that are shared by the various disease-related misfolded proteins” Biochem. And Biophys. Res. Co… [cited by applicant]
Ferreira et al., “α-synuclein interacts with PrPC to induce cognitive impairment through mGluR5 and NMDAR2B” [cited by applicant]
Friberg et al., “Intracerebral Infusion of Antisense Oligonucleotides Into Prion-infected Mice” Mol The Nucl Acids (2012) 1-12. [cited by applicant]
Gautschi et al., “Activity of a novel bcl-2/bcl-xLbispecific antisense oligonucleotide against tumors of diverse histologic origins” J. Natl. Cancer Inst. (2001) 93:463-471. [cited by applicant]
Golding et al., “Suppression of prion protein in livestock by RNA interference” PNAS (2006) 103(14): 5285-5290. [cited by applicant]
International Search Report for PCT/US19/062681 dated Apr. 7, 2020. [cited by applicant]
International Search Report for application PCT/US2009/004680 dated Oct. 13, 2009. [cited by applicant]
Kapuj et al., “Phosphorothioate Oligonucleotides Reduce PrPsc Levels and Prion Infectivity in Cultured Cells” Mol Med (2007) 13(3-4): 190-198. [cited by applicant]
Maher et al., “Comparative hybrid arrest by tandem antisense oligodeoxyribonucleotides or oligodeoxyribonucleoside methylphosphonates in a cell-free system” Nucl. Acid. Res. (1998) 16(8):3341-3358. [cited by applicant]
Mastrianni“The genetics of prion diseases” [cited by applicant]
New England Biolabs 1998/1999 Catalog (cover page and pp. 121 and 284). [cited by applicant]
Ohnishi et al., “Enhancement of Allele Discrimination by Introduction of Nucleotide Mismatches into siRNA in Allele-Specific Gene Silencing by RNAi” PLoS One (2008) 3(5):e2248. [cited by applicant]
Olie et al., “Analysis of ribosyl-modified, mixed backbone analogs of a bcl-2/bcl-xL antisense oligonucleotide” Biochemica et Biophysica Acta (2002) 1576: 101-109. [cited by applicant]
Orru et. al., “Rapid and sensitive RT-QuIC detection of human Creutzfeldt-Jakob disease using cerebrospinal fluid” mBio (2015) 6(1): e02451-14. [cited by applicant]
Pfeifer et al., “Lentivector-mediated RNAi efficiently suppresses prion protein and prolongs survival of scrapie-infected mice” J. Clin. Invest. (2006) 116(12):3204-3210. [cited by applicant]
Purro et al., “Prion Protein as a Toxic Acceptor of Amyloid-β Oligomers” Biol Psychoatry (2018) 83: 358-368. [cited by applicant]
Raymond et al., “Antisense oligonucleotides extend survival of prion-infected mice” JCI Insight (2019) 1-13. [cited by applicant]
Reynolds et al., “Rational siRNA design for RNA interference” Nature Biotechnology (2004) 22(3):326-330. [cited by applicant]
Sanghvi et al., “Heterocyclic Base Modifications in Nucleic Acids and Their Applications in Antisense Oligonucleotides” Antisense Research and Applications (1993) pp. 273-288. [cited by applicant]
Senesi et al., “In vivo prion models and the disconnection between transmissibility and neurotoxicity” [cited by applicant]
Seth et al., “Short Antisense Oligonucleotides with Novel 2′-4′ Conformationaly Restricted Nucleoside Analogues Show Improved Potency Without Increased Toxicity in Animals.” J Med Chem (2009) 52:10-13. [cited by applicant]
Sutou et al., “Knockdown of the bovine prion gene PRNP by RNA interference (RNAi) technology” BMC Biotechnology (2007) 7:44 1-10. [cited by applicant]
Tilly et al., “Efficient and specific down-regulation of prion protein expression by RNAi” Biochemical and Biophysical Research Communications (2003) 305:548-551. [cited by applicant]
Vallabh “Developing an antisense drug for prion disease” downloaded from: http://www.prionalliance.org/2018/07/09/developing-an-antisense-drug-for-prion-disease/ (2018) by scientist at Broad Institute. [cited by applicant]
Weiss et al., “RNA Aptamers Specifically Interact with the Prion Protein PrP” Journal of Virology (1997) 71(11): 8790-8797. [cited by applicant]
White et al., “Single treatment with RNAi against prion protein rescues early neuronal dysfunction and prolongs survival in mice with prion diseases” PNAS (2008) 105(29):10238-10243. [cited by applicant]
Woolf et al., “Specificity of antisense oligonucleotides in vivo” PNAS (1992) 89: 7305-7309. [cited by applicant]
Extended European Search Report for 19888227.6 dated Jan. 5, 2023, 7 pages. [cited by applicant]
International Search Report for PCT/US23/063353 dated Jul. 31, 2023, 19 pages. [cited by applicant]