Combination treatment for the treatment of hepatitis C virus infection
View Patent ↗The present invention relate to the use of a combination of an inhibitor of miR-122 and an inhibitor of VLDL assembly, for the treatment of HCV, hyperlipidemia and hypercholesterolemia.
1. A method of treating Hepatitis C (HCV) infection in a subject infected with HCV, said method comprising the administration of
(i) an effective amount of an inhibitor of miR-122, wherein the inhibitor of miR-122 is an oligonucleotide of sequence 5%-CcAttGTcaCaCtCC-3 (SEQ ID NO: 63), wherein an uppercase letter identifies a beta-D-oxy LNA unit, a lowercase letter identifies a DNA unit, a C identifies a 5-methylcytosine LNA unit, and all internucleoside linkages are phosphorothioate; and,
(ii) an effective amount of an inhibitor of VLDL (very-low-density lipoprotein) assembly.
2. The method according to claim 1 , wherein the inhibitor of VLDL assembly is an inhibitor of ApoB (apolipoprotein B).
3. The method according to claim 2 , wherein the inhibitor of assembly is an antisense compound which targets ApoB.
4. The method according to claim 1 , wherein the inhibitor of VLDL assembly is an inhibitor of MTP (microsomal transfer protein).
5. The method according to claim 1 , wherein the inhibitor of VLDL assembly is a statin.
6. The method according to claim 3 , wherein the inhibitor of VLDL assembly is an antisense oligonucleotide which comprises a nucleobase sequence which is complementary to a corresponding region of an mRNA which encodes a molecule involved in VLDL assembly.
7. The method according to claim 6 , wherein the antisense oligonucleotide which inhibits VLDL assembly has a length of between 9 and 25 nucleobases.
8. The method according to claim 7 , wherein the antisense oligonucleotide which inhibits VLDL assembly is a gapmer oligonucleotide which consists of a nucleobase sequence that is 5′ A-B-C 3′ or 5′ A-B-C-D 3′, wherein:
(i) A comprises between 1 and 5 nucleotide analogue units;
(ii) B comprises 7, 8, 9, 10, 11 or 12 nucleotide units which, when formed in a duplex with a complementary mRNA are capable of recruiting RNAseH;
(iii) C comprises between 1 and 5 nucleotide analogue units; and
(iv) D consists of 1, 2, or 3 DNA units.
9. The method according to claim 8 , wherein all the nucleotide analogue units present in A and C are independently selected from the group consisting of 2′-O-alkyl-RNA units, 2′-OMe-RNA units, 2′-amino-DNA units, 2′ fluoro-DNA units, LNA units, PNA units, HNA units, and INA units.
10. The method according to claim 9 , wherein the nucleotide analogue units present in A and C are all the same.
11. The method according to claim 1 , wherein the miR-122 inhibitor is administered together with the inhibitor of VLDL assembly.
12. The method according to claim 1 , wherein the miR-122 inhibitor and the inhibitor of VLDL assembly are administered separately.
13. The method according to claim 7 , wherein the antisense oligonucleotide which inhibits VLDL assembly has a length of 9, 10, 11, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 nucleobases.
14. The method according to claim 10 , wherein the nucleotide analogue units present in A and C are all LNA units.