Methods of predicting toxicity

Patent metadata

Field	Value
Publication number	US-2016160280-A1
Application number	US-201514932018-A
Country	US
Kind code	A1
Filing date	Nov 4, 2015
Priority date	Dec 1, 2011
Publication date	Jun 9, 2016
Grant date	—

Abstract

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.

First claim

We claim:

1 .- 128 . (canceled)

129 . A method of identifying at least one antisense compound that is predicted not to be toxic in vivo comprising:
identifying a set of potential antisense compounds, each having a nucleobase sequence complementary to a target nucleic acid; comparing the nucleobase sequence of each potential antisense compound to the nucleobase sequence of at least one sentinel gene transcript; identifying potential antisense compounds having a nucleobase sequence complementary to at least one sentinel gene transcript as predicted toxic antisense compounds; removing the predicted toxic compounds from the set of potential antisense compounds; identifying one or more of the remaining potential antisense compounds as predicted not to be toxic in vivo.

130 . The method of claim 129 , wherein the predicted toxic compounds are 90% complementary to at least one sentinel gene transcript.

131 . The method of claim 129 , wherein the predicted toxic compounds are 95% complementary to at least one sentinel gene transcript.

132 . The method of claim 129 , wherein the predicted toxic compounds are 100% complementary to at least one sentinel gene transcript.

133 . The method of claim 129 , wherein the predicted toxic compounds have not more than one mismatch relative to at least one sentinel gene transcript.

134 . The method of claim 129 , wherein the predicted toxic compounds have not more than two mismatches relative to at least one sentinel gene transcript.

135 . The method of claim 129 , wherein each potential antisense compound is compared to the nucleobase sequence of at least two sentinel gene transcripts.

136 . The method of claim 129 , wherein each potential antisense compound is compared to the nucleobase sequence of at least three sentinel gene transcripts.

137 . The method of claim 129 , wherein at least one sentinel gene is selected from the group consisting of Fbx117, Fto, Gphn, Cadps2, Bcas3, Msi2, BC057079, Chn2, Tbc1d22a, Macrod1, Iqgap2, Vps13b, Atg10, Fggy, Odz3, Vps53, Cgnl1, RAPTOR, Ptprk, Vti1a, Ubac2, Fars2, Ppm1l, Adk, 0610012H03Rik, Itpr2, Sec1512///Exoc6b, Atp9b, Atxn1, Adcy9, Mcph1, Ppp3ca, Bre, Dus41, Rassf1, Mdm2, Brp16, 0610010K14Rik, Rce1, Ilf2, Setd1a, and Gar1.

138 . The method of claim 129 , wherein at least one sentinel gene is selected from the group consisting of RAPTOR, Ppp3ca, Fto, Iqgap2, Ptprk, and Adk.

139 . The method of claim 130 , wherein at least one sentinel gene is selected from the group consisting of Fbx117, Fto, Gphn, Cadps2, Bcas3, Msi2, BC057079, Chn2, Tbc1d22a, Macrod1, Iqgap2, Vps13b, Atg10, Fggy, Odz3, Vps53, Cgnl1, RAPTOR, Ptprk, Vti1a, Ubac2, Fars2, Ppm1l, Adk, 0610012H03Rik, Itpr2, Sec1512///Exoc6b, Atp9b, Atxn1, Adcy9, Mcph1, Ppp3ca, Bre, Dus41, Rassf1, Mdm2, Brp16, 0610010K14Rik, Rce1, Ilf2, Setd1a, and Gar1.

140 . The method of claim 130 , wherein at least one sentinel gene is selected from the group consisting of RAPTOR, Ppp3ca, Fto, Iqgap2, Ptprk, and Adk.

141 . The method of claim 134 , wherein at least one sentinel gene is selected from the group consisting of Fbx117, Fto, Gphn, Cadps2, Bcas3, Msi2, BC057079, Chn2, Tbc1d22a, Macrod1, Iqgap2, Vps13b, Atg10, Fggy, Odz3, Vps53, Cgnl1, RAPTOR, Ptprk, Vti1a, Ubac2, Fars2, Ppm1l, Adk, 0610012H03Rik, Itpr2, Sec1512///Exoc6b, Atp9b, Atxn1, Adcy9, Mcph1, Ppp3ca, Bre, Dus41, Rassf1, Mdm2, Brp16, 0610010K14Rik, Rce1, Ilf2, Setd1a, and Gar1.

142 . The method of claim 134 , wherein at least one sentinel gene is selected from the group consisting of RAPTOR, Ppp3ca, Fto, Iqgap2, Ptprk, and Adk.

143 . The method of claim 129 , wherein the antisense 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.

144 . The method of claim 143 , wherein the oligomeric compound comprises at least one modified nucleoside.

145 . The method of claim 144 , wherein the modified nucleoside is a bicyclic modified nucleoside.

146 . The method of claim 145 , wherein the bicyclic modified nucleoside is an LNA.

147 . The method of claim 145 , wherein the bicyclic modified nucleoside is a 4′-CH(CH 3 )—O-2′ nucleoside.

148 . The method of claim 145 , wherein the bicyclic modified nucleoside is an ENA.

Assignees

• Isis Pharmaceuticals Inc

Inventors

• Burel Sebastian

Classifications

• C12Q2600/136

  Screening for pharmacological compounds · CPC title

• C12Q2600/158

  Expression markers · CPC title

• C12Q2600/16

  Primer sets for multiplex assays · CPC title

• C12Q1/6883 Primary

  for diseases caused by alterations of genetic material · CPC title

• C12Q2600/142

  Toxicological screening, e.g. expression profiles which identify toxicity · CPC title