- EFFECTS OF APOLIPOPROTEIN B INHIBITION ON GENE EXPRESSION PROFILES IN ANIMALS
-
Antisense compounds, compositions and methods are provided for modulating the expression of apolipoprotein B. The compositions comprise antisense compounds, particularly antisense oligonucleotides, targeted to nucleic acids encoding apolipoprotein B. Methods of using these compounds for modulation of apolipoprotein B expression and for treatment of diseases associated with expression of apolipoprotein B are provided. Methods are provided for modulating the expression of genes involved in lipid metabolism, useful in the treatment of conditions associated with cardiovascular risk. Antisense oligonucleotides targeted to apolipoprotein B reduce the level of apolipoprotein B mRNA, lower serum cholesterol and shift liver gene expression profiles from those of an obese animal towards those of a lean animal. Further provided are methods for improving the cardiovascular risk of a subject through antisense inhibition of apolipoprotein B. Also provided are methods for employing antisense oligonucleotides targeted to apolipoprotein B to modulate a cellular pathway or metabolic process.
- -
-
-
- Antisense modulation of inducible nitric oxide synthase expression
-
Antisense compounds, compositions and methods are provided for modulating the expression of inducible nitric oxide synthase. The compositions comprise antisense compounds, particularly antisense oligonucleotides, targeted to nucleic acids encoding inducible nitric oxide synthase. Methods of using these compounds for modulation of inducible nitric oxide synthase expression and for treatment of diseases associated with expression of inducible nitric oxide synthase are provided.
- -
-
-
- Antisense modulation of TFAP2C expression
-
Antisense compounds, compositions and methods are provided for modulating the expression of TFAP2C. The compositions comprise antisense compounds, particularly antisense oligonucleotides, targeted to nucleic acids encoding TFAP2C. Methods of using these compounds for modulation of TFAP2C expression and for treatment of diseases associated with expression of TFAP2C are provided.
- -
-
-
- Antisense modulation of histone deacetylase 4 expression
-
Antisense compounds, compositions and methods are provided for modulating the expression of Histone deacetylase 4. The compositions comprise antisense compounds, particularly antisense oligonucleotides, targeted to nucleic acids encoding Histone deacetylase 4. Methods of using these compounds for modulation of Histone deacetylase 4 expression and for treatment of diseases associated with expression of Histone deacetylase 4 are provided.
- -
-
Page/Page column 19
(2010/02/06)
-
- Antisense modulation of P2X4 expression
-
Antisense compounds, compositions and methods are provided for modulating the expression of P2X4. The compositions comprise antisense compounds, particularly antisense oligonucleotides, targeted to nucleic acids encoding P2X4. Methods of using these compounds for modulation of P2X4 expression and for treatment of diseases associated with expression of P2X4 are provided.
- -
-
-
- Synthesis of 2′O-[2-[(N,N-dimethylamino)oxy]ethyl] modified nucleosides and oligonucleotides
-
A versatile synthetic route has been developed for the synthesis of 2′-O-[2-[(N,N-dimethylamino)oxy]ethyl] (abbreviated as 2′-O-DMAOE) modified purine and pyrimidine nucleosides and their corresponding nucleoside phosphoramidites and solid supports. To synthesize 2′-O-n DMAOE purine nucleosides, the key intermediate B (Scheme 1) was obtained from the 2′-O-allyl purine nucleosides (13a and 15) via oxidative cleavage of the carbon-carbon bond to the corresponding aldehydes followed by reduction. To synthesize pyrimidine nucleosides, opening the 2,2′-anhydro-5-methyluridine 5 with the borate ester of ethylene glycol gave the key intermediate B. The 2′-O-(2hydroxyethyl) nucleosides were converted, in excellent yield, by a regioselective Mitsunobu reaction, to the corresponding 2′-O-[2-[(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)oxy]ethyl] nucleosides (18, 19, and 20). These compounds were subsequently deprotected and converted into the 2′-O-[2[(methyleneamino)oxy]ethyl] derivatives (22, 23, and 24). Reduction and a second reductive amination with formaldehyde yielded the corresponding 2′-O-[2-[(N,N-dimethylamino)oxy]ethyl] nucleosides (25, 26, and 27). These nucleosides were converted to their 3′-O-phosphoramidites and controlled-pore glass solid supports in excellent overall yield. Using these monomers, modified oligonucleotides containing pyrimidine and purine bases were synthesized with phosphodiester, phosphorothioate, and both linkages (phosphorothioate and phosphodiester) present in the same oligonucleotide as a chimera in high yields. The oligonucleotides were characterized by HPLC, capillary gel electrophoresis, and ESMS. The effect of this modification on the affinity of the oligonucleotides for complementary RNA and on nuclease stability was evaluated. The 2′-O-DMAOE modification enhanced the binding affinity of the oligonucleotides for the complementary RNA (and not for DNA). The modified oligonucleotides that possessed the phosphodiester backbone demonstrated excellent resistance to nuclease with t1/2 > 24 h.
- Prakash, Thazha P.,Kawasaki, Andrew M.,Fraser, Allister S.,Vasquez, Guillermo,Manoharan, Muthiah
-
p. 357 - 369
(2007/10/03)
-
- 2'-O-[2-[N,N-(dialkyl)aminooxy]ethyl]-modified antisense oligonucleotides.
-
[structure] Oligonucleotides with two novel modifications, 2'-O-2-[N, N-(dimethyl)aminooxy]ethyl (2'-O-DMAOE) and 2'-O-2-[N, N-(diethyl)aminooxy]ethyl (2'-O-DEAOE), have been synthesized. These modifications exhibit high binding affinity to target RNA (and not to DNA) and enhance the nuclease stability of oligonucleotides considerably with t(1/2) > 24 h as a phosphodiester.
- Prakash,Manoharan,Kawasaki,Lesnik,Owens,Vasquez
-
p. 3995 - 3998
(2007/10/03)
-
- Antisense inhibition of Smad5 expression
-
Antisense compounds, compositions and methods are provided for modulating the expression of Smad5. The compositions comprise antisense compounds, particularly antisense oligonucleotides, targeted to nucleic acids encoding Smad5. Methods of using these compounds for modulation of Smad5 expression and for treatment of diseases associated with expression of Smad5 are provided.
- -
-
-