Print Version

New. Geary RS, Wancewicz E, Matson J, Pearce M, Siwkowski A, Swayze E, Bennett F. Effect of Dose and Plasma Concentration on Liver Uptake and Pharmacologic Activity of a 2'-Methoxyethyl Modified Chimeric Antisense Oligonucleotide Targeting PTEN. Biochem Pharmacol. 2009 Aug;78(3):284-91.

New. Geary RS. Antisense Oligonucleotide Pharmacokinetics and Metabolism. Expert Opin Drug Metab Toxicol. 2009 April;5(4):381-91.

New. Fong LG, Vickers TA, Farber EA, Choi C, Yun UJ, Hu Y, Yang SH, Coffinier C, Lee R, Yin L, Davies BS, Andres DA, Spielmann HP, Bennett CF, Young SG. Activating the Synthesis of Progerin, the Mutant Prelamin A in Hutchinson-Gilford Progeria Syndrome, with Antisense Oligonucleotides. Hum Mol Genet . 2009 July;18(13):2462-71.

New. Swarbrick MM, Havel PJ, Levin AA, Bremer AA, Stanhope KL, Butler M, Booten SL, Graham JL, McKay RA, Murray SF, Watts LM, Monia BP, Bhanot S. Inhibition of Protein Tyrosine Phosphatase-1B (PTP-1B) with Antisense Oligonucleotides Improves Insulin Sensitivity and Increases Adiponectin Concentrations in Monkeys. Endocrinology. 2009 April;150(4):1670-9.

New. Andreakos E, Rauchhaus U, Stavropoulos A, Endert G, Wendisch V, Benahmed AS, Giaglis S, Karras J, Lee S, Gaus H, Bennett CF, Williams RO, Sideras P, Panzner S. Amphoteric Liposomes Enable Systemic Antigen-Presenting Cell-Directed Delivery of CD40 Antisense and are Therapeutically Effective in Experimental Arthritis. Arthritis Rheum. 2009 March;60(4):994-1005.

New. Nagai Y, Yonemitsu S, Erion DM, Iwasaki T, Stark R, Weismann D, Dong J, Zhang D, Jurczak MJ, Loeffler MG, Cresswell J, Yu XX, Murray SF, Bhanot S, Monia BP, Bogan JS, Samuel V, Shulman GI. The Role of Peroxisome Proliferator-Activated Receptor gamma Coactivator-1 beta in the Pathogenesis of Fructose-Induced Insulin Resistance. Cell Metab. 2009 March;9(3):252-64.

New. Yu RZ, Lemonidis KM, Graham MJ, Matson J, Crooke RM, Tribble D, Wedel M, Levin AA, Geary RS. Cross-species Comparison of In Vivo PK/PD Relationships for Second Generation Antisense Oligonucleotides Targeting Apolipoprotein B-100. Biochem Pharmacol. 2009 March;77(5):910-919.

New. Kaiser JP, Beier JI, Zhang J, David Hoetker J, von Montfort C, Guo L, Zheng Y, Monia BP, Bhatnagar A, Arteel GE. PKCepsilon Plays a Causal Role in Acute Ethanol-induced Steatosis. Arch Biochem Biophys . 2009 February;482(1-2):104-11.

New. Rimkunas VM, Graham MJ, Crooke RM, Liscum L. TNF-alpha Plays a Role in Hepatocyte Apoptosis in Niemann Pick Type C Liver Disease. J Lipid Res. 2009 Feb;50(2):327-33.

New. Singh R, Wang Y, Xiang Y, Tanaka KE, Gaarde WA, Czaja MJ. Differential Effects of JNK1 and JNK2 Inhibition on Murine Steatohepatitis and Isulin Resistance. Hepatology. 2009 January;49:87-96.

New. Davis S, Propp S, Freier S, Jones L, Serra M, Kinberger G, Bhat B, Swayze E, Bennett F, Esau C. Potent Inhibition of microRNA in vivo without Degradation. Nucleic Acids Res. 2009 January;37(1):70-7.

New. Seth PP, Siwkowski A, Allerson CR, Vasquez G, Lee S, Prakash TP, Wancewicz EV, Witchell D, Swayze EE. Short Antisense Oligonucleotides with Novel 2'-4' Conformationaly Restricted Nucleoside Analogues Show Improved Potency Without Increased Toxicity in Animals. J. Med. Chem. 2009 January;52(1):10-3.

New. Yu RZ, Geary RS, Flaim JD, Riley GC, Tribble DL, vanVliet AA, Wedel MK. Lack of Pharmacokinetic Interaction of Mipomersen Sodium (ISIS 301012), a 2'-O-Methoxyethyl Modified Antisense Oligonucleotide Targeting Apolipoprotein B-100 Messenger RNA, with Simvastatin and Ezetimibe. Clinical Pharmacokinetics. 2009 January;48(1):39-50.

New. Lima WF, Murray H, Nichols JG, Wu H, Sun H, Prakash TP, Berdeja AR, Gaus HJ, Crooke ST. Human Dicer Binds Short Single-strand and Double-strand RNA with High Affinity and Interacts with Different Regions of the Nucleic Acids. J Biol Chem. 2009 January;284(4):2535-48.

New. Newberry EP, Kennedy SM, Xie Y, Luo J, Stanley SE, Semenkovich CF, Crooke RM, Graham MJ, Davidson NO. Altered Hepatic Triglyceride Content after Partial Hepatectomy without Impaired Liver Regeneration in Multiple Murine Genetic Models. Hepatology. 2008 October;48(4):1097-105.

New. Wilusz JE, Freier SM, Spector DL. 3' End Processing of a Long Nuclear-retained Noncoding RNA Yields a tRNA-like Cytoplasmic RNA. Cell. 2008 November;135(5):919-932.

New. Narita S, So A, Ettinger S, Hayashi N, Muramaki M, Fazli L, Kim Y, Gleave M. GL12 Knockdown Using an Antisense Oligonucleotide Induces Apoptosis and Chemosensitizes Cells to Paclitaxel in Androgen-Independent Prostate Cancer. Clinical Cancer Res. 2008 September;14:5769-5777.

Antisense Pharmacology - Proof of Mechanism and Mechanisms of Action

General Antisense Review:

Antisense Drug Discovery

Asthma

Crosby JR, Guha M, Tung D, Miller DA, Bender B, Condon TP, York-Defalco C, Geary RS, Monia BP, Karras JG, Gregora SA. Inhaled CD86 Antisense Oligonucleotide Suppresses Pulmonary Inflammation and Airway Hyper-responsiveness in Allergic Mice. J Pharmacol Exp Ther. 2007 June;321(3):938-46.

Karras, J. G., McGraw, K., McKay, R. A., Cooper, S. R., Lerner, D., Lu, T., Walker, C., Dean, N. M., and Monia, B. P. Inhibition of antigen-induced eosinophilia and late phase airway hyperresponsiveness by an il-5 antisense oligonucleotide in mouse models of asthma. J Immunol. 164(10):5409-5415, 2000.

Cardiovascular

Yu RZ, Lemonidis KM, Graham MJ, Matson J, Crooke RM, Tribble D, Wedel M, Levin AA, Geary RS. Cross-species Comparison of In Vivo PK/PD Relationships for Second Generation Antisense Oligonucleotides Targeting Apolipoprotein B-100. Biochem Pharmacol. 2009 March;77(5):910-919.

Yu RZ, Geary RS, Flaim JD, Riley GC, Tribble DL, vanVliet AA, Wedel MK. Lack of Pharmacokinetic Interaction of Mipomersen Sodium (ISIS 301012), a 2'-O-Methoxyethyl Modified Antisense Oligonucleotide Targeting Apolipoprotein B-100 Messenger RNA, with Simvastatin and Ezetimibe. Clinical Pharmacokinetics. 2009 January;48(1):39-50.

Merki E, Graham MJ, Mullick AE, Miller ER, Crooke RM, Pitas RE, Witztum JL, Tsimikas S. Antisense Oligonucleotide Directed to Human Apolipoprotein B-100 Reduces Lipoprotein(a) Levels and Oxidized Phospholipids on Human Apolipoprotein B-100 Particles in Lipoprotein(a) Transgenic Mice. Circulation. 2008 August;118:743-753.

Graham MJ, Lemonidis KM, Whipple CP, Subramaniam A, Monia BP, Crooke ST, Crooke RM. Antisense Inhibition of Proprotein Convertase Subtilisin Kexin 9 Reduces Serum LDL in Hyperlipidemic Mice. J Lipid Res. 2007 Jan 24.

Zhang YL, Hernandez-Ono A, Siri P, Weisberg S, Conlon D, Graham MJ, Crooke RM, Huang LS, Ginsberg HN. Aberrant Hepatic Expression of PPAR{gamma}2 Stimulates Hepatic Lipogenesis in a Mouse Model of Obesity, Insulin Resistance, Dyslipidemia, and Hepatic Steatosis. J Biol Chem. 2006 Dec 8;281(49):37603-15.

Kastelein JJ, Wedel MK, Baker BF, Su J, Bradley JD, Yu RZ, Chuang E, Graham MJ, Crooke RM. Potent reduction of apolipoprotein B and low-density lipoprotein cholesterol by short-term administration of an antisense inhibitor of apolipoprotein B. Circulation. 2006 Oct 17;114(16):1729-35.

Burnett JR. Drug evaluation: ISIS-301012, an antisense oligonucleotide for the treatment of hypercholesterolemia. Curr Opin Mol Ther. 2006 Oct;8(5):461-7.

Bell TA 3rd, Brown JM, Graham MJ, Lemonidis KM, Crooke RM, Rudel LL. Liver-specific inhibition of acyl-coenzyme a:cholesterol acyltransferase 2 with antisense oligonucleotides limits atherosclerosis development in apolipoprotein B100-only low-density lipoprotein receptor-/- mice. Arterioscler Thromb Vasc Biol. 2006 Aug;26(8):1814-20.

Crooke RM, Graham MJ, Lemonidis KM, Whipple CP, Koo S, Perera RJ. An apolipoprotein B antisense oligonucleotide lowers LDL cholesterol in hyperlipidemic mice without causing hepatic steatosis. J. Lipid Res. 2005; 46: 872-884.

Metabolic

Swarbrick MM, Havel PJ, Levin AA, Bremer AA, Stanhope KL, Butler M, Booten SL, Graham JL, McKay RA, Murray SF, Watts LM, Monia BP, Bhanot S. Inhibition of Protein Tyrosine Phosphatase-1B (PTP-1B) with Antisense Oligonucleotides Improves Insulin Sensitivity and Increases Adiponectin Concentrations in Monkeys. Endocrinology. 2009 April;150(4):1670-9.

Nagai Y, Yonemitsu S, Erion DM, Iwasaki T, Stark R, Weismann D, Dong J, Zhang D, Jurczak MJ, Loeffler MG, Cresswell J, Yu XX, Murray SF, Bhanot S, Monia BP, Bogan JS, Samuel V, Shulman GI. The Role of Peroxisome Proliferator-Activated Receptor gamma Coactivator-1 beta in the Pathogenesis of Fructose-Induced Insulin Resistance. Cell Metab. 2009 March;9(3):252-64.

Kaiser JP, Beier JI, Zhang J, David Hoetker J, von Montfort C, Guo L, Zheng Y, Monia BP, Bhatnagar A, Arteel GE. PKCepsilon Plays a Causal Role in Acute Ethanol-induced Steatosis. Arch Biochem Biophys . 2009 February;482(1-2):104-11.

Singh R, Wang Y, Xiang Y, Tanaka KE, Gaarde WA, Czaja MJ. Differential Effects of JNK1 and JNK2 Inhibition on Murine Steatohepatitis and Isulin Resistance. Hepatology. 2009 January;49:87-96.

Newberry EP, Kennedy SM, Xie Y, Luo J, Stanley SE, Semenkovich CF, Crooke RM, Graham MJ, Davidson NO. Altered Hepatic Triglyceride Content after Partial Hepatectomy without Impaired Liver Regeneration in Multiple Murine Genetic Models. Hepatology. 2008 October;48(4):1097-105.

Yu XX, Murray SF, Watts L, Booten SL, Tokorcheck J, Monia BP, Bhanot S. Reduction of JNK1 expression with antisense oligonucleotide improves adiposity in obese mice. Am J Physiol Endocrinol Metab. 2008 August;295(2):E436-45.

Yu XX, Pandey SK, Booten SL, Murray SF, Monia BP, Bhanot S. Reduced adiposity and improved insulin sensitivity in obese mice with antisense suppression of 4E-BP2 expression. Am J Physiol Endocrinol Metab. 2008 March;294(3):E530-9.

Yamaguchi K, Yang L, McCall S, Huang J, Yu XX, Pandey SK, Bhanot S, Monia BP, Li YX, Diehl AM. Diacylglycerol acyltransferase 1 anti-sense oligonucleotides reduce hepatic fibrosis in mice with nonalcoholic steatohepatitis. Hepatology. 2008 February;47(2):625-635.

Pandey SK, Yu XX, Watts LM, Michael MD, Sloop KW, RIvard AR, Leedon TA, Manchem VP, Samadzadeh L, McKay RA, Monia BP, Bhanot S. Reduction of Low Molecular Weight Protein-Tyrosine Phosphatase Expression Improves Hyperglycemia and Insulin Sensitivity in Obese Mice. J Bio Chem. 2007 May;282(19):14291-9.

Samuel VT, Liu ZX, Wang A, Beddow SA, Geisler JG, Kahn M, Zhang XM, Monia BP, Bhanot S, Shulman GI. Inhibition of Protein Kinase Cepsilon Prevents Hepatic Insulin Resistance in Nonalcoholic Fatty Liver Disease. J Clin Invest. 2007 Mar 1;117(3):739-745.

Samuel VT, Choi CS, Phillips TG, Romanelli AJ, Geisler JG, Bhanot S, McKay R, Monia B, Shutter JR, Lindberg RA, Shulman GI, Veniant MM. Targeting foxo1 in mice using antisense oligonucleotide improves hepatic and peripheral insulin action. Diabetes. 2006 Jul;55(7):2042-50.

Esau C, Davis S, Murray SF, Yu XX, Pandey SK, Pear M, Watts L, Booten SL, Graham M, McKay R, Subramaniam A, Propp S, Lollo BA, Freier S, Bennett CF, Bhanot S, Monia BP. miR-122 regulation of lipid metabolism revealed by in vivo antisense targeting.
Cell Metab. 2006 Feb;3(2):87-98.

Yu XX, Murray SF, Pandey SK, Booten SL, Bao D, Song XZ, Kelly S, Chen S, McKay R, Monia BP, Bhanot S. Antisense oligonucleotide reduction of DGAT2 expression improves hepatic steatosis and hyperlipidemia in obese mice.Hepatology. 2005 Aug;42(2):362-71.

Butler, M., McKay, R.A., Popoff, I.J., Gaarde, W.A., Witchell, D., Murray, S.F., Dean, N.M., Bhanot, S., and Monia, B.P. Specific inhibition of PTEN expression reverses hyperglycemia in diabetic mice. Diabetes. 51(4):1028-34, 2002.

Rondinone, C.M., Trevillyan, J.M., Clampit, J., Gum, R.J., Berg, C., Kroeger, P., Frost, L., Zinker, B.A., Reilly, R., Ulrich, R., Butler, M., Monia, B.P., Jirousek, M.R., and Waring, J.F. Protein tyrosine phosphatase 1B reduction regulates adiposity and expression of genes involved in lipogenesis. Diabetes. 2002 Aug;51(8):2405-11.

Zinker, B.A., Rondinone, C.M., Trevillyan, J.M., Gum, R.J., Clampit, J.E., Waring, J.F., Xie, N., Wilcox, D., Jacobson, P., Frost, L., Kroeger, P.E., Reilly, R.M., Koterski, S., Opgenorth, T.J., Ulrich, R.G., Crosby, S., Butler, M., Murray, S.F., McKay, R.A., Bhanot, S., Monia, B.P., and Jirousek, M.R. PTP1B antisense oligonucleotides lowers PTP1B protein, normalizes blood glucose, and improved insulin sensitivity in diabetic mice. Proc. Natl. Acad. Sci. USA 99 (17): 11357-11362, 2002.

Inflammatory Diseases

Andreakos E, Rauchhaus U, Stavropoulos A, Endert G, Wendisch V, Benahmed AS, Giaglis S, Karras J, Lee S, Gaus H, Bennett CF, Williams RO, Sideras P, Panzner S. Amphoteric Liposomes Enable Systemic Antigen-Presenting Cell-Directed Delivery of CD40 Antisense and are Therapeutically Effective in Experimental Arthritis. Arthritis Rheum. 2009 March;60(4):994-1005.

Rimkunas VM, Graham MJ, Crooke RM, Liscum L. TNF-alpha Plays a Role in Hepatocyte Apoptosis in Niemann Pick Type C Liver Disease. J Lipid Res. 2009 Feb;50(2):327-33.

Myers, K.J., Murthy, S., Flanigan, A., Witchell, D.R., Butler, M., Murray, S., Siwkowski, A., Goodfellow, D., Madsen, K., Baker, B. Antisense oligonucleotide blockade of tumor necrosis factor-alpha in two murine models of colitis. J Pharmacol Exp Ther. 304(1):411-424, 2003.

Bowen-Yacyshyn, M.B., Bennett, C.F., Nation, N., Raynor, D., and Yacyshyn, B.R. Amelioration of chronic and spontaneous intestinal inflammation with an antisense oligonucleotide (ISIS 9125) to ICAM-1 in the HLA-B27/2 microglobulin transgenic rat model. J Pharmacol Exp Ther. 2002 Sep;302(3):908-17.

Bennett, C. F., Kornbrust, D., Henry, S., Stecker, K., Howard, R., Cooper, S., Dutson, S., Hall, W., and Jacoby, H. I. An icam-1 antisense oligonucleotide prevents and reverses dextran sulfate sodium-induced colitis in mice. J Pharmacol Exp Ther. 280(2):988-1000, 1997.

Oncology

Narita S, So A, Ettinger S, Hayashi N, Muramaki M, Fazli L, Kim Y, Gleave M. GL12 Knockdown Using an Antisense Oligonucleotide Induces Apoptosis and Chemosensitizes Cells to Paclitaxel in Androgen-Independent Prostate Cancer. Clinical Cancer Res. 2008 September;14:5769-5777.

Unal R, Pokrovskaya I, Tripathi P, Monia BP, Kern PA, Ranganathan G. Translational Regulation of Lipoprotein Lipase in Adipocytes: Depletion of Cellular Protein Kinase Calpha Activates Binding of the C Subunit of Protein Kinase A to the 3'-untranslated Region of the Lipoprotein Lipase mRNA. Biochem J. 2008 July;413(2):315-22.

Saberi B, Shinohara M, Ybanez MD, Hanawa N, Gaarde WA, Kaplowitz N, Han D. Regulation of H(2)O(2)-induced Necrosis by PKC and AMP-activated Kinase Signaling in Primary Cultured Hepatocytes. Am J Physiol Cell Physiol. 2008 July;295(1):C50-63.

Graff JR, Konicek BW, Konicek W, Carter JH, Marcusson EG. Targeting the Eukaryotic Translation Initiation Factor 4E for Cancer Therapy. Cancer Res. 2008 February;68(3):631-634

Graff JR, Konicek BW, Vincent TM, Lynch RL, Monteith D, Weir SN, Schwier P, Capen A, Goode RL, Dowles MS, Chen Y, Zhang H, Sissons S, Cox K, McNulty AN, Parsons SH, Wang T, Sams L, Geeganage S, Douglass LE, Neubauer BL, Dean NM, Blanchard K, Shou J, Stancato LF, Carter JH, Marcusson EG. Therapeutic Suppression of Translation Initiation Factor eIF4E Expression Reduces Tumor Growth Without Toxicity. J Clin Invest. 2007 September;117:2638-2648.

Dagvadorj A, Collins S, Jomain JB, Abdulghani J, Karras J, Zellweger T, Li H, Nurmi M, Alanen K, Mirtti T, Visakorpi T., Budendorf L, Goffin V, Nevalainen MT. . Autocrine Prolactin Promotes Prostate Cancer Cell Growth via Jak2-Stat5a/b Signaling Pathway. Endocrinology. 2007 July ;148(7):3089-101.

Kim Y, Yoon JW, Xiao X, Dean NM, Monia BP, Marcusson EG. Selective Down-regulation of Glioma-associated Oncogene 2 Inhibits the Proliferation of Hepatocellular Carcinoma Cells. Cancer Res. 2007 Apr 15;67(8):3583-93.

Koller E, Propp S, Zhang H, Zhao C, Xiao X, Chang M, Hirsch SA, Shepard PJ, Koo S, Murphy C, Glazer RI, Dean NM. Use of a Chemically Modified Antisense Oligonucleotide Library to Identify and Validate Eg5 (Kinesin-Like 1) as a Target for Antineoplastic Drug Development. Cancer Res. 2006 Feb 15;66(4):2059-2066.

Chi KN, Eisenhauer E, Fazli L, Jones EC, Goldenberg SL, Powers J, Tu D, Gleave ME. A phase I pharmacokinetic and pharmacodynamic study of OGX-011, a 2'-methoxyethyl antisense oligonucleotide to clusterin, in patients with localized prostate cancer. J Natl Cancer Inst. 2005 Sep 7;97(17):1287-96.

Yang, Y.M., Bost, F., Charbono, W., Dean, N., McKay, R., Rhim, J.S., Depatie, C., Mercola, D. C-Jun NH(2)-terminal kinase mediates proliferation and tumor growth of human prostate carcinoma. Clin Cancer Res. 2003 Jan;9(1):391-401.

Pedersen, I.M., Kitada, S., Leoni, L.M., Zapata, J.M., Karras, J.G., Tsukada, N., Kipps, T.J., Choi, Y.S., Bennett, F., Reed, J.C. Protection of CLL B cells by a follicular dendritic cell line is dependent on induction of Mcl-1. Blood. 2002 Sep 1;100(5):1795-801.

Fennell, D.A., Corbo, M.V., Dean, N.M., Monia, B.P., and Cotter, F.E. In Vivo Expression of bcl-xl expression facilitates chemotherapy-induced leukemia cell death in a scid/nod-hu model. Br J Haematol. 112(3): 706-713, 2001.

Bulavin, D.V., Higashimoto, Y., Popoff, I.J., Gaarde, W.A., Basrur, V., Potapova, O. Appella, E., and Fornace, Jr., A.J. Initiation of a G2/M checkpoint after ultraviolet radiation requires p38 kinase. Nature. 2001 May 3;411(6833):102-7.

Mesri, M., Morales-Ruiz, M., Ackermann, E. J., Bennett, C. F., Pober, J. S., Sessa, W. C., and Altieri, D. C. Suppression of vascular endothelial growth factor-mediated endothelial cell protection by survivin targeting. Am J Pathol. 158(5):1757-1765, 2001.

Zellweger, T., Miyake, H., Cooper, S., Chi, K., Conklin, B.S., Monia, B.P., and Gleave, M.E. Antitumor activity of antisense clusterin oligonucleotides is improved in vitro and in vivo by incorporation of 2'-o-(2-methoxyethyl). J Pharmacol Exp Ther. 298(3): 934-940, 2001.

Li, F., Ackermann, E.J., Bennett, C.F., Rothermel, A.L., Plescia, J., Tognin, S., Villa, A., Marchisio, P.C., and Altieri, D.C. Pleiotropic cell-division defects and apoptosis induced by interference with survivin function. Nature Cell Biol. 1:461-466, 1999.

Anti-viral

Detrick, B., Nagineni, C.N., Grillone, L.R., Anderson, K.P., Henry, S.P., and Hooks, J.J. Inhibition of human cytomegalovirus replication in human retinal epitheal cell model by antisense oligonucleotide. Invest Ophthalmol Vis Sci. 2001 Jan;42(1):163-9.

Zhang, H., Cook, J., Nickel, J., Yu, R., Stecker, K., Myers, K., and Dean, N. M. Reduction of liver fas expression by an antisense oligonucleotide protects mice from fulminant hepatitis. Nat Biotechnol. 18(8):862-867, 2000.

Zhang, H., Hanecak, R., Brown-Driver, V., Azad, R., Conklin, B., Fox, M. C., and Anderson, K. P. Antisense oligonucleotide inhibition of hepatitis c virus (hcv) gene expression in livers of mice infected with an hcv-vaccinia virus recombinant. Antimicrobial Agents and Chemotherapy. 43(2):347-353, 1999.

Hanecak, R., Brown-Driver, V., Fox, M.C., Azad, R.F., Furusako, S. Nozaki, C., Ford, C., Sasmor, H., Anderson, K.P. Antisense oligonucleotide inhibition of hepatitis c virus gene expression in transformed hepatocytes. Journal of Virology. 70(8):5203-5212, 1996.

Central Nervous System

Kim DH, Fitzsimmons B, Hefferan MP, Svensson CI, Wancewicz E, Monia BP, Hung G, Butler M, Marsala M, Hua XY, Yaksh TL . Inhibition of Spinal Cytosolic Phospholipase A(2) Expression by an Antisense Oligonucleotide Attenuates Tissue Injury-induced Hyperalgesia. Neuroscience. 2008 June;154(3):1077-87.

Hua Y, Vickers TA, Baker BF, Bennett CF, Krainer AR. Enhancement of SMN2 Exon 7 Inclusion by Antisense Oligonucleotides Targeting the Exon. PLoS Biol. 2007 April;5(4):729-744.

Smith RA, Miller TM, Yamanaka K, Monia BP, Condon TP, Hung G, Lobsiger CS, Ward CM, McAlonis-Downes M, Wei H, Wancewicz EV, Bennett CF, Cleveland DW. Antisense oligonucleotide therapy for neurodegenerative disease. J Clin Invest. 2006 Aug;116(8):2290-6. Epub 2006 Jul 27.

Ocular

Danis R, Criswell M, Orge F, Wancewicz E, Stecker K, Henry S, Monia B. Intravitreous anti-raf-1 kinase antisense oligonucleotide as an angioinhibitory agent in porcine preretinal neovascularization. Curr Eye Res. 2003 Jan;26(1):45-54

Danis RP, Henry SP, Ciulla TA. Potential therapeutic application of antisense oligonucleotides in the treatment of ocular diseases. Expert Opin Pharmacother. 2001 Feb;2(2):277-91

Antisense Pharmacokinetics

Geary RS, Wancewicz E, Matson J, Pearce M, Siwkowski A, Swayze E, Bennett F. Effect of Dose and Plasma Concentration on Liver Uptake and Pharmacologic Activity of a 2'-Methoxyethyl Modified Chimeric Antisense Oligonucleotide Targeting PTEN. Biochem Pharmacol. 2009 April 21 [Epub ahead of print].

Geary RS. Antisense Oligonucleotide Pharmacokinetics and Metabolism. Expert Opin Drug Metab Toxicol. 2009 April;5(4):381-91.

Yu RZ, Lemonidis KM, Graham MJ, Matson J, Crooke RM, Tribble D, Wedel M, Levin AA, Geary RS. Cross-species Comparison of In Vivo PK/PD Relationships for Second Generation Antisense Oligonucleotides Targeting Apolipoprotein B-100. Biochem Pharmacol. 2009 March;77(5):910-919.

Yu RZ, Geary RS, Flaim JD, Riley GC, Tribble DL, vanVliet AA, Wedel MK. Lack of Pharmacokinetic Interaction of Mipomersen Sodium (ISIS 301012), a 2'-O-Methoxyethyl Modified Antisense Oligonucleotide Targeting Apolipoprotein B-100 Messenger RNA, with Simvastatin and Ezetimibe. Clinical Pharmacokinetics. 2009 January;48(1):39-50.

Yu RZ, Kim TW, Hong A, Watanabe TA, Gaus HJ, Geary RS. Cross-Species Pharmacokinetic Comparison from Mouse to Man of a Second-Generation Antisense Oligonucleotide, ISIS 301012, Targeting Human Apolipoprotein B-100. Drug Metab Dispos. 2007 Mar;35(3):460-8. Epub 2006 Dec. 15.

Geary, R. S., Khatsenko, O., Bunker, K., Crooke, R., Moore, M., Burckin, T., Truong, L., Sasmor, H., and Levin, A. A. Absolute bioavailability of 2'-o-(2-methoxyethyl)-modified antisense oligonucleotides following intraduodenal instillation in rats. J Pharmacol Exp Ther. 296(3):898-904, 2001.

Geary, R. S., Watanabe, T. A., Truong, L., Freier, S., Lesnik, E. A., Sioufi, N. B., Sasmor, H., Manoharan, M., and Levin, A. A. Pharmacokinetic properties of 2'-o-(2-methoxyethyl)-modified oligonucleotide analogs in rats. J Pharmacol Exp Ther. 296(3):890-897, 2001.

Yu, R. Z., Zhang, H., Geary, R. S., Graham, M., Masarjian, L., Lemonidis, K., Crooke, R., Dean, N. M., and Levin, A. A. Pharmacokinetics and pharmacodynamics of an antisense phosphorothioate oligonucleotide targeting fas mrna in mice. J Pharmacol Exp Ther. 296(2):388-395, 2001.

Butler, M., Crooke, R.M., Graham, M.J., Lemonidis, K.M., Lougheed, M., Murray, S.F., Witchell, D., Steinbrecher, U., Bennet, C.F. Phosphorothioate oligodeoxynucleotides distribute similarly in class a scavenger receptor knockout and wild-type mice. J Pharmacol Exp Ther. 292(2):489-496, 2000.

Graham, M.J., Crooke, S. T., Monteith, D. K., Cooper, S. R., Lemonidis, K. M., Stecker, K. K., Martin, M. J., and Crooke, R. M. In vivo distribution and metabolism of a phosphorothioate oligonucleotide within rat liver after intravenous administration. J Pharmacol. Exp Ther. 286(1):447-458, 1998.

Butler, M., Stecker, K., and Bennett, C. F. Cellular distribution of phosphorothioate oligodeoxynucleotides in normal rodent tissues. Lab Invest. 77(4):379-388, 1997.

Antisense Safety Profile

Levin, A., Henry, S., Monteith, D., and Templin, M. Toxicity of antisense oligonucleotides. Antisense Drug Technology: Principles, Strategies, and Applications (ed. Crooke, S.T.), pp. 201-267. Marcel Dekker, Inc., New York, 2001.

Dorr, A., Glover, J., and Kwoh, J. Clinical safety of phosphorothioate oligodeoxynucleotides. Antisense Drug Technology: Principles, Strategies, and Applications (ed. Crooke, S.T.), pp. 269-290. Marcel Dekker, Inc., New York, 2001.

Henry, S., Stecker, K., Brooks, D., Monteith, D., Conklin, B., and Bennett, C. F. Chemically modified oligonucleotides exhibit decreased immune stimulation in mice. J Pharmacol Exp Ther. 292(2):468-479, 2000.

Antisense Evidence of Clinical Activity

Alicaforsen (ISIS 2302)

Miner PB Jr, Wedel MK, Xia S, Baker BF. Safety and efficacy of two dose formulations of alicaforsen enema compared with mesalazine enema for treatment of mild to moderate left-sided ulcerative colitis: a randomized, double-blind, active-controlled trial. Aliment Pharmacol Ther. 2006 May 15;23(10):1403-13.

Miner PB Jr, Geary RS, Matson J, Chuang E, Xia S, Baker BF, Wedel MK. Bioavailability and therapeutic activity of alicaforsen (ISIS 2302) administered as a rectal retention enema to subjects with active ulcerative colitis. Aliment Pharmacol Ther. 2006 May 15;23(10):1427-34.

van Deventer SJ, Wedel MK, Baker BF, Xia S, Chuang E, Miner PB Jr. A phase II dose ranging, double-blind, placebo-controlled study of alicaforsen enema in subjects with acute exacerbation of mild to moderate left-sided ulcerative colitis. Aliment Pharmacol Ther. 2006 May 15;23(10):1415-25.

Yacyshyn, B.R., Chey, W.Y., Goff, J., Salzberg, B. Baerg, R., Buchman, A.L., Tami, J., Yu, R., Gibiansky, E., and Shanahan, W.R. Double blind, placebo controlled trial of the remission inducing and steroid sparing properties of an ICAM-1 antisense oligodeoxynucleotide, Alicaforsen (ISIS 2302), in active steroid dependent Crohn’s disease. Gut. 51: 30-36, 2002.

Shanahan, W. ISIS 2302, an antisense inhibitor of intercellular adhesion molecule 1 (ICAM-1). In: Antisense Drug Technology: Principles, Strategies, and Applications (ed. Crooke, S.T.), pp. 773-794. Marcel Dekker, Inc., New York, 2001.

Yacyshyn, B.R., Bowen-Yacyshyn, M.B., Jewell, L., Tami, J.A., Bennett, C.F., Kisner, D.L., and Shanahan, Jr., W.R. A placebo-controlled trial of ICAM-1 antisense oligonucleotide in the treatment of Crohn's disease. Gastroenterology. 1998 Jun;114(6):1133-42.

ISIS 104838

Sewell, K.L., Geary, R.S., Baker, B.F., Glover, J.M., Mant, T.G., Yu, R.Z., Tami, J.A., and Dorr, A. Phase I trial of ISIS 104838, a 2'-Methoxyethyl modified antisense oligonucleotide targeting tumor necrosis factor-a. J Pharmacol Exp Ther. 2002 Dec;303(3):1334-43.

Vitravene

Vitravene Study Group. A randomized controlled clinical trial of intravitreous fomivirsen for treatment of newly diagnosed peripheral cytomegalovirus retinitis in patients with AIDS. American Journal of Ophthalmology 133(4): 467-474, 2002.

Vitravene Study Group. Randomized dose-comparison studies of intravitreous fomivirsen for treatment of cytomegalovirus retinitis that has reactivated or is persistently active despite other therapies in patients with AIDS. American Journal of Ophthalmology 133(4): 475-483, 2002.

Vitravene Study Group. Safety of intravitreous fomivirsen of treatment of cytomegalovirus retinitis in patients with AIDS. American Journal of Ophthalmology 133(4): 484-498, 2002.

Grillone, L.R. and Lanz, R. Fomivirsen. Drugs Today (Barc). 2001 Apr;37(4):245-255.

Medicinal Chemistry/Formulations of Antisense Oligonucleotides

Seth PP, Siwkowski A, Allerson CR, Vasquez G, Lee S, Prakash TP, Wancewicz EV, Witchell D, Swayze EE. Short Antisense Oligonucleotides with Novel 2'-4' Conformationaly Restricted Nucleoside Analogues Show Improved Potency Without Increased Toxicity in Animals. J. Med. Chem. 2009 January;52(1):10-3.

Tillman LG, Geary RS, Hardee GE. Oral delivery of antisense oligonucleotides in man. J Pharm Sci. 2008 Jan;97(1):225-236.

Bijsterbosch, M.K., Manoharan, M., Dorland, R., Van Veghel, R., Biessen, E.A., Van Berkel, T.J. bis-Cholesteryl-conjugated phosphorothioate oligodeoxynucleotides are highly selectively taken up by the liver. J Pharmacol Exp Ther. 302(2):619-26, 2002.

Maier, M.A., Leeds, J.M., Balow, G., Springer, R.H., Bharadwaj, R., and Manoharan, M. Nuclease resistance of oligonucleotides containing the tricyclic cytosine analogues phenoxazine and 9-(2-aminoethoxy)-phenoxazine (""G-clamp"") and origins of their nuclease resistance properties. Biochemistry. 2002 Jan 29;41(4):1323-7.

Cook, P. D. Medicinal chemistry of antisense oligonucleotides. Antisense drug technology: Principles, strategies, and applications (ed. Crooke, S. T.), pp. 29-56. Marcel Dekker, New York, 2001.

Karras J.G., Maier, M.A., Lu, T., Watt, A., Manoharan, M. Peptide Nucleic acids are potent modulators of endogenous pre-mrna splicing of the murine interleukin-5 receptor-alpha chain. Biochemistry. 2001 Jul 3;40(26):7853-9.

Manoharan, M. Oligonucleotide conjugates in antisense technology. Antisense drug technology: Principles, strategies, and applications (ed. Crooke, S. T.), pp. 391-470. Marcel Dekker, New York, 2001.

Sazani, P., Kang, S.H., Maier, M.A., Wei, C., DillmAn, J., Manoharan, M., Kole, R., Nuclear antisense effects of neutral anionic and cationic oligonucleotide analogues. Nucleic Acid Res. (29) 19: 3965-3974, 2001.

Mehta, R.C., Stecker, K.K., Cooper, S.R., Templin, M.V., Tsai, Y.J., Condon, T.P., Bennett, C.F., Hardee, G.E. Intercellular adhesion molecule-1 suppression in skin by topical delivery of anti-sense oligonucleotides. J Invest Dermatol.115(5):805-812, 2000.

Templin, M. V., Levin, A. A., Graham, M. J., Aberg, P. M., Axelsson, B. I., Butler, M., Geary, R. S., and Bennett, C. F. Pharmacokinetic and toxicity profile of a phosphorothioate oligonucleotide following inhalation delivery to lung in mice. Antisense Nucleic Acid Drug Dev. 10(5):359-368, 2000.

Antisense Oligonucleotide Manufacturing

Wang Z, Olsen P, Ravikumar VT. A Novel Universal Linker for Efficient Synthesis of Phosphorothioate Oligonucleotides. Nucleosides Nucleotides Nucleic Acids. 2007;26(3):259-69.

Krotz, A. H., Cole, D.L. , Ravikumar, V. T. Synthesis of antisense oligonucleotides with minimum depurination. Nucleosides Nucleotides Nucleic Acids. 22(2):129-34, 2003.

Pon, R.T., Yu, S., Sanghvi, Y.S. Multiple oligonucleotides synthesis in tandem on solid-phase supports for small and large scale synthesis. Nucleosides Nucleotides Nucleic Acids. 20(4-7):985-989, 2001.

Sanghvi, Y.S., Ravikumar, VT., Scozzari, A.N., Cole, D.L. Applications of green chemistry in the manufacture of oligonucleotide drugs. Pure App Chem. 73(1):175-180, 2001.