RNAi therapy for hepatitis B virus infection
Described are compositions and methods for inhibition of Hepatitis B virus gene expression. RNA interference (RNAi) triggers and RNAi trigger conjugates for inhibiting the expression of Hepatitis B virus gene are described. Pharmaceutical compositions comprising one or more HBV RNAi triggers optionally with one or more additional therapeutics are also described. Delivery of the described HBV RNAi triggers to infected liver in vivo provides for inhibition of HBV gene expression and treatment.
1. A composition comprising: an HBV RNAi trigger comprising an antisense strand and a sense strand wherein the antisense strand comprises nucleotides 2-18 of a modified antisense sequences selected from the group consisting of SEQ ID NOS: 210, 211, 214, 215, 218, 220, 221, 230-237, 242-244, 247, 260, 261, 264, 265 and 319 and wherein the sense strand comprises a modified sequence selected from the group consisting of SEQ ID NOS: 415, 416, 420, 425, 427, 446, 470, 473, 474, 477, 492, 556 and 557.
2. The composition of claim 1 wherein the sense strand is conjugated to a galactose trimer.
3. The composition of claim 2 , wherein the galactose trimer comprises an N-acetylgalactosamine.
4. The composition of claim 1 , wherein the HBV RNAi trigger comprises a duplex selected from the group consisting of AD00003 (SEQ ID NOS: 210 and 415), AD00009 (SEQ ID NOS: 210 and 420), AD00078 (SEQ ID NOS: 210 and 427), AD00079 (SEQ ID NOS: 210 and 425), AD01129 (SEQ ID NOS: 210 and 446), AD00004 (SEQ ID NOS: 211 and 416), AD01497 (SEQ ID NOS: 211 and 492), AD01382 (SEQ ID NOS: 244 and 470), AD01386 (SEQ ID NOS: 244 and 474), AD03154 (SEQ ID NOS: 244 and 557), AD01385 (SEQ ID NOS: 247 and 473), AD01389 (SEQ ID NOS: 247 and 477), AD03153 (SEQ ID NOS: 247 and 556), AD01438 (SEQ ID NOS: 260 and 474), AD01461 (SEQ ID NOS: 261 and 473).
5. The composition of claim 4 , wherein the HBV RNAi trigger comprises the duplex AD01385 (SEQ ID NOS: 247 and 473) or AD01386 (SEQ ID NOS: 244 and 474).
6. The composition of claim 1 , further comprising a pharmaceutically acceptable excipient.
7. The composition of claim 6 , wherein the pharmaceutically acceptable excipient comprises dextran.
8. The composition of claim 1 , further comprising one or more additional therapeutics.
9. The composition of claim 1 , wherein the composition further comprises:
MLP-(L-T) x ,
wherein:
MLP is a melittin-like peptide,
-L-T has the structure represented by —CO—C(CH 3 )═C(T)-COOH or —CO—C(T)=C(CH 3 )—COOH, wherein T comprises a targeting ligand having affinity for the an asialoglycoprotein receptor, and
x is greater than 80% of the number of primary amines of a population of MLPs.