Methods of predicting toxicity
View Patent ↗Described herein are compounds useful for the treatment and investigation of diseases, methods for the prediction of in vivo toxicity of compounds useful for the treatment and investigation of diseases, and methods of discovering and identifying compounds useful for the treatment and investigation of diseases that have reduced in vivo toxicity.
1. A method of predicting the in vivo toxicity of an oligomeric compound, wherein the method comprises:
contacting a cell in vitro with the oligomeric compound; and
measuring the modulation of the amount or activity of at least two sentinel genes, wherein the modulation of the amount or activity of the at least two sentinel genes correlates with toxicity in vivo.
2. The method of claim 1 , wherein the oligomeric compound comprises a gapmer oligonucleotide consisting of 10 to 30 linked nucleosides, wherein the gapmer oligonucleotide has a 5′ wing region positioned at the 5′ end of a deoxynucleotide gap, and a 3′ wing region positioned at the 3′ end of the deoxynucleotide gap.
3. The method of claim 2 , wherein each of the wing regions is between about 1 to about 7 nucleotides in length.
4. The method of claim 2 , wherein each of the wing regions is between about 1 to about 3 nucleotides in length.
5. The method of claim 2 , wherein the deoxy gap region is between about 7 to about 18 nucleotides in length.
6. The method of claim 2 , wherein the deoxy gap region is between about 11 to about 18 nucleotides in length.
7. The method of claim 2 , wherein the deoxy gap region is between about 7 to about 10 nucleotides in length.
8. The method of claim 2 , wherein the oligomeric compound comprises at least one modified nucleoside.
9. The method of claim 8 , wherein the modified nucleoside is a bicyclic modified nucleoside.
10. The method of claim 8 , wherein the bicyclic modified nucleoside is a locked nucleic acid (LNA) nucleoside.
11. The method of claim 8 , wherein the bicyclic modified nucleoside is a constrained ethyl (cEt) nucleoside.
12. The method of claim 8 , wherein the modified nucleoside is a 2′-modified nucleoside.
13. The method of claim 12 , wherein the 2′-modified nucleoside is substituted at the 2′ position with a substituted or unsubstituted —O-alkyl or substituted or unsubstituted —O-(2-acetylamide), wherein the non-bicyclic 2′-modified nucleoside comprises a 2′-OCH 3 , 2′O(CH 2 ) 2 OCH 3 , or 2′-OCH 2 C(O)—NR 1 R 2 , wherein R 1 and R 2 are independently hydrogen or substituted or unsubstituted alkyl or, in the alternative, are taken together to make a heterocyclic moiety.