Gene silencing of cardiovascular genes

Abstract

We disclose bispecific nucleic acid molecules comprising at least two double stranded inhibitory ribonucleic acid (RNA) molecules adapted to silence by RNA interference either the same gene or different genes to enhance silencing thereby modulating gene expression wherein said at least two double stranded inhibitory RNA molecules are linked by a DNA linker molecule; and a treatment regimen comprising administration of at least two inhibitory monospecific RNA molecules adapted to silence at least two cardiovascular gene targets.

Description

[0001] GENE SILENCING OF CARDIOVASCULAR GENES

[0002] Field of the Disclosure

[0003] The disclosure relates to bispecific nucleic acid molecules comprising at least two double stranded inhibitory ribonucleic acid (RNA) molecules adapted to silence by RNA interference either the same gene or different genes to enhance silencing thereby modulating gene expression wherein said at least two double stranded inhibitory RNA molecules are linked by a DNA linker molecule; and a treatment regimen comprising administration of at least two inhibitory monospecific RNA molecules adapted to silence at least two cardiovascular gene targets.

[0004] Sequence Listing

[0005] The instant application contains a Sequence Listing which has been submitted herewith and is hereby incorporated by reference in its entirety.

[0006] Background to the Disclosure

[0007] A technique to specifically ablate gene function is through the introduction of double stranded inhibitory RNA, also referred to as small inhibitory or interfering RNA (siRNA), into a cell which results in the destruction of mRNA complementary to the sequence included in the siRNA molecule. The siRNA molecule comprises two complementary strands of RNA (a sense strand and an antisense strand) annealed to each other to form a double stranded RNA molecule. The siRNA molecule is typically, but not exclusively, derived from exons of the gene which is to be ablated. Many organisms respond to the presence of double stranded RNA by activating a cascade that leads to the formation of siRNA. The presence of double stranded RNA activates a protein complex comprising RNase III which processes the double stranded RNA into smaller fragments (siRNAs, approximately 21-29 nucleotides in length) which become part of a ribonucleoprotein complex. The siRNA acts as a guide for the RNase complex to cleave mRNA complementary to the antisense strand of the siRNA thereby resulting in destruction of the mRNA.

[0008] Typically, RNA silencing utilises a single siRNA species directed to a single gene to silence expression. It is known to link siRNAs to enable the silencing of two or more genes. For example, W02016205410 discloses oligonucleotides linked together directly, via functional end-substitutions, or indirectly by way of a linking agent. The oligonucleotide can be bound directly to a linker. Such bonding can be achieved, for example, through use of 3'-thionucleosides. WO2018145086 discloses oligonucleotides in the form of a multimeric oligonucleotide having monomeric subunits of oligonucleotide joined by covalent linkers to decrease clearance due to glomerular filtration. W02013040429A1 discloses multi-oligomeric complexes that comprise two or more targeting oligonucleotides linked together by a cleavable linker. WO2015113922 discloses oligo oligonucleotides conjugates where two or more antisense oligonucleotides are covalently linked by physiologically labile linkers, and to a biocleavable functional group such as a conjugate group. W02010141511 discloses bivalent or multivalent nucleic acid molecules or complexes of nucleic acid molecules having two or more target-specific regions, in which the target-specific regions are complementary to a single target gene at more than one distinct nucleotide site, and / or in which the target regions are complementary to more than one target gene or target sequence. WO2017188707 discloses a dicer substrate RNA nanostructure exhibiting enhanced gene silencing effects. The RNA nanostructure includes a plurality of the same or different RNAi sequences in a single RNA nanostructure. The use of oligomeric nanostructures comprising more than one siRNA or antisense molecule is known in the art. W02017 / 015109 discloses multi-targeted nucleic acid constructs comprising at least two inhibitory RNAs that are covalently linked by nucleic acid linkers via the 3’ ends of sense and antisense strands of corresponding inhibitory RNAs.

[0009] There is a desire to provide alternative and simpler approaches to the delivery of more than one inhibitory RNA to a cell with the objective of silencing the expression of one or more gene targets to obtain enhanced therapeutic effects. In our currently unpublished PCT application PCT / GB2024 / 051168, the content of which is incorporated by reference it its entirety, there is disclosure of dual silencing constructs comprising a short DNA linker molecule that silences two cardiovascular gene targets in the liver of mice and is efficacious. This disclosure relates to the identification of variant DNA linker molecules that stably link at least two siRNAs, for example and not by way of limitation, genes associated with cardiovascular disease, that silence expression of the same target gene or different target gene to modulate gene expression simultaneously or co-ordinately.

[0010] STATEMENT OF INVENTION

[0011] According to an aspect of the invention there is provided a nucleic acid molecule comprising: i) a first nucleic acid comprising a double stranded inhibitory ribonucleic acid (RNA) molecule comprising a sense and an antisense strand designed with reference to a nucleotide sequence comprising a gene to be silenced and wherein there is provided a first single stranded deoxyribonucleic acid (DNA) molecule conjugated to either the 5’ or 3’ end of said sense or antisense strand; and

[0012] ii) a second nucleic acid comprising a double stranded inhibitory ribonucleic acid (RNA) molecule comprising a sense and an antisense strand designed with reference to a different or the same gene to be silenced as set forth in i) above and wherein there is provided a second single stranded deoxyribonucleic acid (DNA) molecule conjugated to either the 5’ or 3’ end of said sense or antisense strand wherein the second single stranded deoxyribonucleic acid (DNA) molecule is substantially complementary to the first single stranded deoxyribonucleic acid (DNA) molecule set forth in i) above and anneals by complementary base pairing to form a double stranded DNA linker that links the first and second double stranded inhibitory ribonucleic acid (RNA) molecules wherein said DNA linker molecule comprises a nucleotide sequence having a melting temperature (TM) that is 73°C + / - 5%.

[0013] In a preferred embodiment of the invention said DNA linker molecule comprises a nucleotide sequence wherein the TM is about 69°C to 76°C.

[0014] In a preferred embodiment of the invention said DNA linker molecule comprises a nucleotide sequence wherein the TM is about 73°C.

[0015] In a preferred embodiment of the invention said first single stranded deoxyribonucleic acid (DNA) molecule comprises the nucleotide sequence: 5’ CGAAGCG 3’.

[0016] In a preferred embodiment of the invention said single stranded DNA comprises the nucleotide sequence 5’ CGAAGCGCCCTACTCCACT 3’ (SEQ ID NO: 17155).

[0017] Preferably said complementary single stranded DNA comprises the nucleotide sequence 5’ AGTGGAGTAGGGCGCTTCG 3’ (SEQ ID NO: 17156).

[0018] In a preferred embodiment of the invention said single stranded DNA comprises the nucleotide sequence CGAAGCGCCCTACTCCACT (SEQ ID NO: 17155) and is attached to the 5’ end of the sense nucleotide sequence. In a preferred embodiment of the invention said complementary single stranded DNA comprises the nucleotide sequence AGTGGAGTAGGGCGCTTCG (SEQ ID NO: 17156) and is attached to the 5’ end of the sense nucleotide sequence.

[0019] According to an aspect or embodiment of the invention there is provided a nucleic acid molecule comprising:

[0020] i) a first nucleic acid comprising a double stranded inhibitory ribonucleic acid (RNA) molecule comprising a sense and an antisense strand designed with reference to a nucleotide sequence comprising a gene to be silenced and wherein there is provided a first single stranded deoxyribonucleic acid (DNA) molecule conjugated to either the 5’ or 3’ end of said sense or antisense strand; and

[0021] ii) a second nucleic acid comprising a double stranded inhibitory ribonucleic acid (RNA) molecule comprising a sense and an antisense strand designed with reference to a different or the same gene to be silenced as set forth in i) above and wherein there is provided a second single stranded deoxyribonucleic acid (DNA) molecule conjugated to either the 5’ or 3’ end of said sense or antisense strand wherein the second single stranded deoxyribonucleic acid (DNA) molecule is substantially complementary to the first single stranded deoxyribonucleic acid (DNA) molecule set forth in i) above and anneals by complementary base pairing to form a double stranded DNA linker that links the first and second double stranded inhibitory ribonucleic acid (RNA) molecules wherein said DNA linker molecule is not

[0022] 5’ CGAAGCGCCCTACTCCACT 3’ (SEQ ID NO: 17155)

[0023] 3’ GCTTCGCGGGATGAGGTGA 5’ (SEQ ID NO: 17156)

[0024] wherein the DNA linker molecule comprises a nucleotide sequence having a melting temperature (TM) that is 73°C + / - 5%.

[0025] In a preferred embodiment of the invention said DNA linker molecule comprises a nucleotide sequence wherein the TM is about 69°C to 76°C.

[0026] In a preferred embodiment of the invention said DNA linker molecule comprises a nucleotide sequence wherein the TM is about 73°C.

[0027] In a preferred embodiment of the invention said first single stranded deoxyribonucleic acid (DNA) molecule comprises the nucleotide sequence: CGAAGCG. In a preferred embodiment of the invention said first single stranded DNA molecule comprises a nucleotide sequence selected from the group: SEQ ID NO: 1 to SEQ ID NO: 6170.

[0028] In a preferred embodiment of the invention said second single stranded complementary DNA molecule is selected from the group: SEQ ID NO: 6171 to SEQ ID NO: 12340 and is fully complementary to said first single stranded DNA molecule as set forth in SEQ ID NO: 1 to SEQ ID NO: 6170 and is a stable double stranded DNA linker molecule.

[0029] Preferably said stable double stranded DNA linker molecule has a TM of about 73°C.

[0030] In a preferred embodiment of the invention said a single stranded deoxyribonucleic acid (DNA) is linked to said first or second double stranded inhibitory RNA molecule wherein said linkage is selected from the group:

[0031] i) 5’ sense strand of said first double stranded inhibitory RNA and 5’ antisense stand of said second double stranded inhibitory RNA molecule;

[0032] ii) 5’ sense strand of said first double stranded inhibitory RNA and 3’ sense strand of said second double stranded inhibitory RNA molecule;

[0033] iii) 5’ sense strand of said first double stranded inhibitory RNA and 5’ sense strand of said second double stranded inhibitory RNA molecule; iv) 5’ sense strand of said first double stranded inhibitory RNA and the 3’ antisense strand of said second double stranded inhibitory RNA molecule;

[0034] v) 3’ sense strand of said first double stranded inhibitory RNA and the 5’ sense strand of said second double stranded inhibitory RNA molecule;

[0035] vi) 3’ sense strand of said first double stranded inhibitory RNA and the 3’ sense strand of said second double stranded inhibitory RNA molecule;

[0036] vii) 3’ sense strand of said first double stranded inhibitory RNA and the 5’ antisense strand of said second double stranded inhibitory RNA molecule;

[0037] viii) 3’ sense strand of said first double stranded inhibitory RNA and the 3’ antisense of said second double stranded inhibitory RNA molecule;

[0038] ix) 5’ antisense strand of said first double stranded inhibitory RNA and the 5’ sense strand of said second double stranded inhibitory RNA molecule;

[0039] x) 5’ antisense strand of said first double stranded inhibitory RNA and the 3’ sense strand of said second double stranded inhibitory RNA molecule;

[0040] xi) 5’ antisense strand of said first double stranded inhibitory RNA and the 5’ antisense strand of said second double stranded inhibitory RNA molecule; xii) 5’ antisense strand of said first double stranded inhibitory RNA and the 3’ antisense strand of said second double stranded inhibitory RNA molecule;

[0041] xiii) 3’ antisense strand of said first double stranded inhibitory RNA and the 5’ sense strand of said second double stranded inhibitory RNA molecule;

[0042] xiv) 3’ antisense strand of said first double stranded inhibitory RNA and the 3’ sense strand of said second double stranded inhibitory RNA molecule;

[0043] xv) 3’ antisense strand of said first double stranded inhibitory RNA and the 3’ antisense of said second double stranded inhibitory RNA molecule; and

[0044] xvi) 3’ antisense strand of said first double stranded inhibitory RNA and the 5’ antisense of said second double stranded inhibitory RNA molecule.

[0045] In a preferred embodiment of the invention said the first and second gene to be silenced is the same gene.

[0046] In an alternative preferred embodiment of the invention said first and second gene to be silenced are different genes.

[0047] In a preferred embodiment of the invention said first and second double stranded inhibitory RNA molecules comprise different nucleotide sequences.

[0048] In a preferred embodiment of the invention said first or second gene to be silenced is the apolipoprotein B (Apo B) gene.

[0049] In a preferred embodiment of the invention said Apo B gene comprises a nucleotide sequence set forth in SEQ ID NO: 12341 wherein said double stranded inhibitory RNA is 19-23 nucleotides in length.

[0050] In a preferred embodiment of the invention said Apo B double stranded inhibitory RNA comprise or consists of a sense nucleotide sequence selected from the group: SEQ ID NO: 12947-13246.

[0051] In a preferred embodiment of the invention said Apo B double stranded inhibitory RNA comprise or consists of an antisense nucleotide sequence selected from the group: SEQ ID NO: 13247-13546.

[0052] In an alternative preferred embodiment of the invention said first or second gene to be silenced is proprotein convertase subtilisin / kexin type 9 (PCSK9). In a preferred embodiment of the invention said PCSK9 gene comprises a nucleotide sequence set forth in SEQ ID NO: 12342 wherein said double stranded inhibitory RNA is 19-23 nucleotides in length.

[0053] In a preferred embodiment of the invention said double stranded PCSK9 inhibitory RNA comprise or consists of a sense nucleotide sequence selected from the group: SEQ ID NO: 13547-13850 and SEQ ID NO 17161.

[0054] In a preferred embodiment of the invention said double stranded PCSK9 inhibitory RNA comprise or consists of an antisense nucleotide sequence selected from the group: SEQ ID NO: 13851-14154 and 17162.

[0055] In a further alternative embodiment of the invention said first or second gene to be silenced is lipoprotein A (Lp(a)).

[0056] In a preferred embodiment of the invention said Lp(a) gene comprises a nucleotide sequence set forth in SEQ ID NO: 12343 wherein said double stranded inhibitory RNA is 19-23 nucleotides in length.

[0057] In a preferred embodiment of the invention said Lp(a) double stranded inhibitory RNA comprise or consists of a sense nucleotide sequence selected from the group: SEQ ID NO: 14155-14454 and 17163.

[0058] In a preferred embodiment of the invention said Lp(a) double stranded inhibitory RNA comprise or consists of an antisense nucleotide sequence selected from the group: SEQ ID NO: 14455-14754 and 17164.

[0059] In a further alternative embodiment of the invention said first or second gene to be silenced is angiotensinogen.

[0060] In a preferred embodiment of the invention said angiotensinogen gene comprises a nucleotide sequence set forth in SEQ ID NO: 12344 wherein said double stranded inhibitory RNA is 19-23 nucleotides in length. In a preferred embodiment of the invention said double stranded angiotensinogen inhibitory RNA comprise or consists of a sense nucleotide sequence selected from the group: SEQ ID NO: 14755-15054.

[0061] In a preferred embodiment of the invention said double stranded angiotensinogen inhibitory RNA comprise or consists of an antisense nucleotide sequence selected from the group: SEQ ID NO: 15055-15354.

[0062] In a further alternative preferred embodiment of the invention said first or second gene to be silenced is apolipoprotein CHI (Apo Clll).

[0063] In a preferred embodiment of the invention said Apo Clll gene comprises a nucleotide sequence set forth in SEQ ID NO: 12345 wherein said double stranded inhibitory RNA is 19-23 nucleotides in length.

[0064] In a preferred embodiment of the invention said double stranded Apo Clll inhibitory RNA comprise or consists of a sense nucleotide sequence selected from the group: SEQ ID NO: 15355-15654 and 17200.

[0065] In a preferred embodiment of the invention said double stranded Apo Clll inhibitory RNA comprise or consists of an antisense nucleotide sequence selected from the group: SEQ ID NO: 15655-15954 and 17199.

[0066] In a further alternative preferred embodiment of the invention said first or second gene to be silenced is diacylglycerol acyltransferase 2 (DGAT2).

[0067] In a preferred embodiment of the invention said DGAT2 gene comprises a nucleotide sequence set forth in SEQ ID NO: 12346 wherein said double stranded inhibitory RNA is 19-23 nucleotides in length.

[0068] In a preferred embodiment of the invention said double stranded DGAT2 inhibitory RNA comprise or consists of a sense nucleotide sequence selected from the group: SEQ ID NO: 12348-12646, 17169 and 17171 to 17179.

[0069] In a preferred embodiment of the invention said double stranded DGAT2 inhibitory RNA comprise or consists of an antisense nucleotide sequence selected from the group: SEQ ID NO: 12647-12946, 17170 and 17180 to 17188. In a preferred embodiment of the invention said first or second gene to be silenced is angiopoietin-like protein 3 (ANGPTL3).

[0070] In a preferred embodiment of the invention said ANGPTL3 gene comprises a nucleotide sequence set forth in SEQ ID NO: 17159 wherein said double stranded inhibitory RNA is 19-23 nucleotides in length.

[0071] In a preferred embodiment of the invention said double stranded ANGPTL3 inhibitory RNA comprise or consists of a sense nucleotide sequence selected from the group: SEQ ID NO: 15955-16254, 17165 and 17167.

[0072] In a preferred embodiment of the invention said double stranded ANGPTL3 inhibitory RNA comprise or consists of an antisense nucleotide sequence selected from the group: SEQ ID NO:16255-16554, 17166 and 17168.

[0073] In a preferred embodiment of the invention said first or second gene to be silenced is angiopoietin-related protein 4 (ANGPTL4).

[0074] In a preferred embodiment of the invention said ANGPTL4 gene comprises a nucleotide sequence set forth in SEQ ID NO: 17160 wherein said double stranded inhibitory RNA is 19-23 nucleotides in length.

[0075] In a preferred embodiment of the invention said ANGPTL4 double stranded inhibitory RNA comprise or consists of a sense nucleotide sequence selected from the group: SEQ ID NO: 16555-16854.

[0076] In a preferred embodiment of the invention said ANGPTL4 double stranded inhibitory RNA comprise or consists of an antisense nucleotide sequence selected from the group: SEQ ID NO: 16855-17154.

[0077] In a preferred embodiment of the invention said first or second gene to be silenced is selected from the group consisting of: Apo B, DGAT2, PCSK9, Lp(a), APOCIII, angiotensinogen, ANGPTL3 and ANGPTL4.

[0078] In a preferred embodiment of the invention said first gene is Apo B and said second gene is DGAT2. In a preferred embodiment of the invention said first gene is Apo B and said second gene is PCSK9.

[0079] In a preferred embodiment of the invention said first gene is Apo B and said second gene is angiotensinogen.

[0080] In a preferred embodiment of the invention said first gene is Apo B and said second gene is Apo CHI.

[0081] In a preferred embodiment of the invention said first gene is Apo B and said second gene is Lp(a).

[0082] In a preferred embodiment of the invention said first gene is PCSK9 and said second gene is angiotensinogen.

[0083] In a preferred embodiment of the invention said first gene is PCSK9 and said second gene is Apo CHI .

[0084] In a preferred embodiment of the invention said first gene is PCSK9 and said second gene is DGAT2.

[0085] In a preferred embodiment of the invention said first gene is PCSK9 and said second gene is Lp(a).

[0086] In a preferred embodiment of the invention said first gene is angiotensinogen and said second gene is Apo CHI.

[0087] In a preferred embodiment of the invention said first gene is angiotensinogen and said second gene is DGAT2.

[0088] In a preferred embodiment of the invention said first gene is angiotensinogen and said second gene is Lp(a).

[0089] In a preferred embodiment of the invention said first gene is Apo CHI and said second gene is DGAT2. In a preferred embodiment of the invention said first gene is Apo CHI and said second gene is Lipoprotein (a).

[0090] In a preferred embodiment of the invention said first gene is DGAT2 and said second gene is Lipoprotein (a).

[0091] In a preferred embodiment of the invention said first gene is ANGPLT3 and said second gene is ApoB.

[0092] In a preferred embodiment of the invention said first gene is ANGPLT3 and said second gene is PCSK9.

[0093] In a preferred embodiment of the invention said first gene is ANGPLT3 and said second gene is angiotensinogen.

[0094] In a preferred embodiment of the invention said first gene is ANGPLT3 and said second gene is APOCIII.

[0095] In a preferred embodiment of the invention said first gene is ANGPLT3 and said second gene is Lp(a).

[0096] In a preferred embodiment of the invention said first gene is ANGPLT3 and said second gene is DGAT2.

[0097] In a preferred embodiment of the invention said first gene is ANGPLT3 and said second gene is ANGPLT4.

[0098] In a preferred embodiment of the invention said first gene is ANGPLT4 and said second gene is Apo B.

[0099] In a preferred embodiment of the invention said first gene is ANGPLT4 and said second gene is PCSK9.

[0100] In a preferred embodiment of the invention said first gene is ANGPLT4 and said second gene is angiotensinogen. In a preferred embodiment of the invention said first gene is ANGPLT4 and said second gene is Apo CHI .

[0101] In a preferred embodiment of the invention said first gene is ANGPLT4 and said second gene is Lp(a).

[0102] In a preferred embodiment of the invention said first gene is ANGPLT4 and said second gene is DGAT2.

[0103] In a preferred embodiment of the invention said first and / or said second double stranded inhibitory RNA molecule comprises or consists of natural nucleotides.

[0104] In an alternative preferred embodiment of the invention said first and / or said second double stranded inhibitory RNA molecule comprises modified nucleotides and / or modified sugar(s).

[0105] In a preferred embodiment of the invention said modified nucleotides / sugars are selected from the group: a 3 '-terminal deoxy- thymine (dT) nucleotide, a 2'-0-methyl modified nucleotide, a 2'-fluoro modified nucleotide, a 2'-deoxy-modified nucleotide, a locked nucleotide, an unlocked nucleotide, a conformationally restricted nucleotide, a constrained ethyl nucleotide, an abasic nucleotide, a 2'-amino-modified nucleotide, a 2'-O-allyl-modified nucleotide, 2'-C-alkyl-modified nucleotide, 2' -hydroxyl- modified nucleotide, a 2'-methoxyethyl modified nucleotide, a 2'-0- alkyl-modified nucleotide, a morpholino nucleotide, a phosphoramidate, a non-natural base comprising nucleotide, a tetrahydropyran modified nucleotide, a 1,5-anhydrohexitol modified nucleotide, a cyclohexenyl modified nucleotide, a nucleotide comprising a phosphorothioate group, a nucleotide comprising phosphorodithioate (PS2), a nucleotide comprising a methylphosphonate group, a nucleotide comprising a 5’- phosphate, and a nucleotide comprising a 5 ‘-phosphate mimic, for example a 5’-vinyl phosphate, a nucleotide comprising a 2’-deoxy-2’-fluro and a 2’ methyl sugar base and glycol nucleic acid.

[0106] In a preferred embodiment of the invention said first or and / or second double stranded inhibitory RNA molecule comprises at least one modified nucleotide wherein said modification is 2'-deoxy-2'-fluoro. In a preferred embodiment of the invention said first and / or said second double stranded inhibitory RNA molecule comprises at least one modified nucleotide wherein said modification is 2'-O-methyl.

[0107] In a further preferred embodiment of the invention said first and / or said second double stranded inhibitory RNA molecule comprises at least one phosphorothioate linkage.

[0108] In a further preferred embodiment of the invention said first and / or said second double stranded inhibitory RNA molecule comprises at least one 5'-vinyl phosphate.

[0109] In an embodiment of the invention said first and / or said second double stranded inhibitory RNA molecule comprises at least one modified sugar.

[0110] A sugar modification includes a modified version of the ribosyl moiety, such as -O-modified RNA such as '-O-alkyl or 2'-0-(substituted)alkyl e.g. 2'-0-methyl, T-0-(2-cyanoethyl), 2'-0-(2-methoxy)ethyl (2'-MOE), 2'-0-(2-thiomethyl)ethyl, 2'-0-butyryl, -O-propargyl, 2'-O-allyl, 2'-O-(2-amino)propyl, 2'-O-(2-(dimethylamino)propyl), 2'-O-(2-amino)ethyl, 2'-O-(2-(dimethylamino)ethyl); 2'-deoxy (DNA); 2'-O-(haloalkoxy)methyl, e.g.

[0111] 2'-0-(2-chloroethoxy)methyl (MCEM), -O- (2,2-dichloroethoxy)methyl (DCEM); 2'-<3-alkoxycarbonyl e.g. T-0-[2- (methoxycarbonyl)ethyl] (MOCE), 2'-O-[2-(N-methylcarbamoyl)ethyl] (MCE), T-0-[2-(N,N- dimethylcarbamoyl)ethyl] (DCME); 2'-halo e.g. 2'-F, FANA (2'-F arabinosyl nucleic acid); carbasugar and azasugar modifications; 3 '-O-alkyl e.g. 3'-0-methyl, 3 '-O-butyryl, V-O- propargyl and their derivatives.

[0112] In a preferred embodiment of the invention said first double stranded inhibitory RNA comprises or consists of a sense nucleotide sequence selected from the group:

[0113] i) 5’ CCCTCAACTTTTCTAAACT3’ (SEQ ID NO: 13003)

[0114] ii) 5’GTCCCAGGTAUATTCGAAA3’ (SEQ ID NO: 12968)

[0115] iii) 5’GUUCCAUGUCCCAUUUACA3’ (SEQ ID NO: 12969)

[0116] iv) 5’GCACGUGGGUUCCAAAUUA3’ (SEQ ID NO: 12967)

[0117] v) 5’CAAGGGUGUUAUUUCCAUA3’ (SEQ ID NO: 12986)

[0118] vi) 5’CUCAAGACCCAAUUUAACA3’ (SEQ ID NO: 12999)

[0119] vii) 5’GUACUGUCCCAGGUAUAUU3’ (SEQ ID NO: 12970) viii)5’CCAAUUUCCCUGUGGAUCU3’ (SEQ ID NO:12971)

[0120] ix) 5’GGGUUCCAAAUUAAUAGUU3’ (SEQ ID NO: 13005)

[0121] x) 5’CAGGAAGGGCUCAAAGAAU3’ (SEQ ID NO: 13003)

[0122] xi) 5’GGGAACUGUUGAAAGAUUU3’ (SEQ ID NO: 12951)

[0123] xii) 5’GAAACAACCCAGUCUCAAA3’ (SEQ ID NO: 12993) xiii)5’CCCAUGGUCUUGAGUUAAA3’ (SEQ ID NO: 12957) xiv) 5’ CAAAGUUAAUUGGGAAGAA3’ (SEQ ID NO: 13004)

[0124] xv) 5’CCCUAUUCUCUGGUAACUA3’ (SEQ ID NO: 12977)

[0125] xvi) 5’CAAUGAAGGGAAUUUGAAA3’ (SEQ ID NO: 12961)

[0126] xvii) 5’CCCUGAAGUUGAUGUGUUA3’ (SEQ ID NO: 12947)

[0127] xviii) 5’GAGGGUAGUCAUAACAGUA3’ (SEQ ID NO: 13002) xix)5’CACUAAAUUCCCAUGGUCU3’; and (SEQ ID NO: 12992) or

[0128] xx) 5’ GUACUGGGUUAAUGGUCAA3 (SEQ ID NO: 12959),

[0129] wherein said double stranded inhibitory RNA inhibits the expression of said Apo B gene.

[0130] In a preferred embodiment of the invention said first double stranded inhibitory RNA comprises or consists of an antisense nucleotide sequence selected from the group:

[0131] i) 5’AGUUUAGAAAAGUUGAGGG3’ (SEQ ID NO: 13303)

[0132] ii) 5’UUUCGAAUAUACCUGGGAC3’ (SEQ ID NO: 13268)

[0133] iii) 5’UGUAAAUGGGACAUGGAAC3’ (SEQ ID NO: 13269)

[0134] iv) 5’UAAUUUGGAACCCACGUGC3’ (SEQ ID NO: 13267)

[0135] v) 5’UAUGGAAAUAACACCCUUG3’ (SEQ ID NO: 13286)

[0136] vi) 5’UGUUAAAUUGGGUCUUGAG3’ (SEQ ID NO:13299)

[0137] vii) 5’AAUAUACCUGGGACAGUAC3’ (SEQ ID NO: 13270) viii)5’AGAUCCACAGGGAAAUUGG3’ (SEQ ID NO: 13271)

[0138] ix) 5’AACUAUUAAUUUGGAACCC3’ (SEQ ID NO: 13305)

[0139] x) 5’AUUCUUUGAGCCCUUCCUG3’ (SEQ ID NO: 13278)

[0140] xi) 5’AAAUCUUUCAACAGUUCCC3’ (SEQ ID NO: 13251)

[0141] xii) 5’UUUGAGACUGGGUUGUUUC3’ (SEQ ID NO: 13293) xiii)5’UUUAACUCAAGACCAUGGG3’ (SEQ ID NO: 13257) xiv)5’UUCUUCCCAAUUAACUUUG3’ (SEQ ID NO: 13304)

[0142] xv) 5’UAGUUACCAGAGAAUAGGG3’(SEQ ID NO: 13277) xvi)5’UUUCAAAUUCCCUUCAUUG3’ (SEQ ID NO: 13261)

[0143] xvii) 5’UAACACAUCAACUUCAGGG3’ (SEQ ID NO: 13247)

[0144] xviii) 5’UACUGUUAUGACUACCCUC3’ (SEQ ID NO: 13302) xix)5’AGACCAUGGGAAUUUAGUG3’; and (SEQ ID NO: 13292) or

[0145] xx) 5’UUGACCAUUAACCCAGUAC3’ (SEQ ID NO: 13259),

[0146] wherein said double stranded inhibitory RNA inhibits the expression of said Apo B gene.

[0147] In a preferred embodiment of the invention said Apo B double inhibitory RNA comprises or consists of a sense nucleotide sequence set forth in SEQ ID NO: 5’CCAAUUUCCCUGUGGAUCU3’ (SEQ ID NO: 12971) and corresponding antisense nucleotide sequence set forth in SEQ ID NO: 5’AGAUCCACAGGGAAAUUGG3’ (SEQ ID NO: 13271). In a preferred embodiment of the invention said Apo B double stranded inhibitory RNA comprises or consists of a modified sense and / or antisense nucleotide sequence.

[0148] In a preferred embodiment of the invention said Apo B double stranded inhibitory RNA is modified and comprises one or more 2'-O-methyl moieties.

[0149] In a preferred embodiment of the invention said Apo B double stranded inhibitory RNA is modified and comprises one or more 2'-deoxy-2'-fluoro moieties.

[0150] In a preferred embodiment of the invention said sense nucleotide sequence comprises substantially 2'-O-methyl moieties.

[0151] In a preferred embodiment of the invention said antisense nucleotide sequence comprises substantially 2'-deoxy-2'-fluoro moieties.

[0152] In a preferred embodiment of the invention said sense nucleotide sequence is modified wherein said modification pattern comprises the following:

[0153] 5’mmmmmmfffmmmmmmmmmm3’

[0154] wherein m - 2'-O-methyl and f - 2'-deoxy-2'-fluoro.

[0155] In a preferred embodiment of the invention said antisense nucleotide sequence is modified wherein said modification patter comprises the following:

[0156] 5’mfmfmfmfmfmfmfmfmfm + mllmU3’

[0157] wherein m - 2'-O-methyl and f - 2'-deoxy-2'-fluoro.

[0158] In a preferred embodiment of the invention said second inhibitory RNA comprises or consists of a sense nucleotide sequence wherein said double stranded inhibitory RNA inhibits the expression of the DGAT2 gene.

[0159] In a preferred embodiment of the invention said DGAT2 double stranded inhibitory RNA comprises or consists of a modified sense and / or antisense nucleotide sequence.

[0160] In a preferred embodiment of the invention said DGAT2 double stranded inhibitory RNA is modified and comprises one or more 2'-O-methyl moieties. In a preferred embodiment of the invention said DGAT2 double stranded inhibitory RNA is modified and comprises one or more 2'-deoxy-2'-fluoro moieties.

[0161] In a preferred embodiment of the invention said sense nucleotide sequence comprises substantially 2'-O-methyl moieties.

[0162] In a preferred embodiment of the invention said antisense nucleotide sequence comprises substantially 2'-deoxy-2'-fluoro moieties.

[0163] According to an aspect of the invention there is provided a nucleic acid molecule comprising:

[0164] i) a first nucleic acid comprising a double stranded inhibitory ribonucleic acid (RNA) molecule comprising a sense and an antisense strand with reference to a nucleotide sequence comprising a cardiovascular disease associated gene to be silenced wherein said cardiovascular disease gene is apolipoprotein B (Apo B) and wherein there is provided a first single stranded deoxyribonucleic acid (DNA) molecule conjugated to either the 5’ or 3’ end of said sense or antisense strand; and

[0165] ii) a second nucleic acid comprising a double stranded inhibitory ribonucleic acid (RNA) molecule comprising a sense and an antisense strand with reference to a different cardiovascular disease associated gene to be silenced wherein said cardiovascular disease gene is diacylglycerol O acyltransferase 2 (DGAT2) and wherein there is provided a second single stranded deoxyribonucleic acid (DNA) molecule conjugated to either the 5’ or 3’ end of said sense or antisense strand wherein the second single stranded deoxyribonucleic acid (DNA) molecule is substantially complementary to the first single stranded deoxyribonucleic acid (DNA) molecule set forth in i) above and anneals by complementary base pairing to form a double stranded DNA linker that links the first and second double stranded inhibitory ribonucleic acid (RNA) molecules wherein said DNA linker molecule comprises a nucleotide sequence having a melting temperature (TM) that is 73°C + / - 5%.

[0166] In a preferred embodiment of the invention said DNA linker molecule comprises a nucleotide sequence wherein the TM is about 69°C to 76°C In a preferred embodiment of the invention said DNA linker molecule comprises a nucleotide sequence wherein the TM is about 73°C.

[0167] In a further preferred embodiment of the invention said first single stranded deoxyribonucleic acid (DNA) molecule comprises the nucleotide sequence: 5’ CGAAGCG 3’.

[0168] In a preferred embodiment of the invention said single stranded DNA comprises the nucleotide sequence 5’ CGAAGCGCCCTACTCCACT 3’ (SEQ ID NO: 17155).

[0169] In a further preferred embodiment of the invention said complementary single stranded DNA comprises the nucleotide sequence 5’ AGTGGAGTAGGGCGCTTCG 3’ (SEQ ID NO: 17156).

[0170] In a preferred embodiment of the invention said first single stranded DNA molecule comprises a nucleotide sequence selected from the group: SEQ ID NO: 1 to SEQ ID NO: 6170.

[0171] Preferably, said second single stranded complementary DNA molecule is selected from the group: SEQ ID NO: 6171 to SEQ ID NO: 12340 and is fully complementary to said first single stranded DNA molecule as set forth in SEQ ID NO: 1 to SEQ ID NO: 6170 and is a stable double stranded DNA linker molecule.

[0172] In a preferred embodiment of the invention said Apo B and / or DGAT2 double stranded inhibitory RNA comprises or consists of a modified sense and / or antisense nucleotide sequence.

[0173] Preferably, said Apo B and / or DGAT2 double stranded inhibitory RNA is modified and comprises one or more 2'-O-methyl moieties.

[0174] In a preferred embodiment of the invention said ApoB and / or DGAT2 double stranded inhibitory RNA is modified and comprises one or more 2'-deoxy-2'-fluoro moieties.

[0175] Preferably, said sense nucleotide sequence comprises substantially 2'-O-methyl moieties. Preferably, said antisense nucleotide sequence comprises substantially 2'-deoxy-2'-fluoro moieties.

[0176] In a preferred embodiment of the invention said sense nucleotide sequence is modified wherein said modification pattern comprises the following:

[0177] mmmmmmfffmmmmmmmmmm

[0178] wherein m - 2'-O-methyl and f - 2'-deoxy-2'-fluoro.

[0179] In a preferred embodiment of the invention said antisense nucleotide sequence is modified wherein said modification patter comprises the following:

[0180] mfmfmfmfmfmfmfmfmfm + mUrnll

[0181] wherein m - 2'-O-methyl and f - 2'-deoxy-2'-fluoro.

[0182] In a preferred embodiment of the invention said DGAT2 double stranded inhibitory RNA comprises a sense nucleotide sequence set forth in SEQ IDs presented in Table 16 wherein said double stranded inhibitory RNA is 19-23 nucleotides in length.

[0183] In a preferred embodiment of the invention said DGAT2 double stranded inhibitory RNA comprises an antisense nucleotide sequence set forth in SEQ IDs presented in Table 16 wherein said double stranded inhibitory RNA is 19-23 nucleotides in length.

[0184] In a preferred embodiment of the invention said DGAT2 double stranded inhibitory RNA comprises a sense nucleotide sequence set forth in SEQ IDs presented in Table 17 wherein said double stranded inhibitory RNA is 19-23 nucleotides in length.

[0185] In a preferred embodiment of the invention said DGAT2 double stranded inhibitory RNA comprises an antisense nucleotide sequence set forth in SEQ IDs presented in Table 17 wherein said double stranded inhibitory RNA is 19-23 nucleotides in length.

[0186] In a preferred embodiment of the invention said APOB double stranded inhibitory RNA comprises a sense nucleotide sequence set forth in SEQ IDs presented in Table 18 wherein said double stranded inhibitory RNA is 19-23 nucleotides in length. In a preferred embodiment of the invention said APOB double stranded inhibitory RNA comprises an antisense nucleotide sequence set forth in SEQ IDs presented in Table 18 wherein said double stranded inhibitory RNA is 19-23 nucleotides in length.

[0187] In a preferred embodiment of the invention said APOB double stranded inhibitory RNA comprises a sense nucleotide sequence set forth in SEQ IDs presented in Table 19 wherein said double stranded inhibitory RNA is 19-23 nucleotides in length.

[0188] In a preferred embodiment of the invention said APOB double stranded inhibitory RNA comprises an antisense nucleotide sequence set forth in SEQ IDs presented in Table 19 wherein said double stranded inhibitory RNA is 19-23 nucleotides in length.

[0189] In a preferred embodiment of the invention said double stranded inhibitory RNA comprises sense and antisense nucleotide sequences linked by a double stranded DNA linker wherein said sense nucleotide sequence is:

[0190] 5’_CGAAGCGCCCTACTCCACTmC*mC*mAmAmUmUfUfCfCmCmUmGmUmGmGmA mU*mC*mll / Gal3C2 / 3’; and (SEQ ID NO: 17238)

[0191] said antisense nucleotide sequence is:

[0192] AGTGGAGTAGGGCGCTTCGmG*mU*mCmAmUmGmGmGfUfGfUmCmUmGmUmGm G mGmU*mll*mA / Gal3C2 / 3.’ (SEQ ID NO: 17239)

[0193] In a preferred embodiment of the invention said double stranded inhibitory RNA comprises sense and antisense nucleotide sequences linked by a double stranded DNA linker wherein said sense nucleotide sequence is:

[0194] 5’_CGAAGCGTAGCCGGGGGAAmC*mC*mAmAmUmUfUfCfCmCmUmGmUmGmGmA mU*mC*mU / Gal3C2 / 3’ (SEQ ID NO: 17240)

[0195] and said antisense nucleotide sequence is:

[0196] 5’TTCCCCCGGCTACGCTTCGmG*mU*mCmAmUmGmGmGfUfGfUmCmUmGmUmGm G mGmU*mU*mA / Gal3C2 / 3’. (SEQ ID NO: 17241) In a preferred embodiment of the invention said double stranded inhibitory RNA comprises sense and antisense nucleotide sequences linked by a double stranded DNA linker wherein said sense nucleotide sequence is:

[0197] 5’_CGAAGCGTGACGGGGTCGAmC*mC*mAmAmUmUfUfCfCmCmUmGmUmGmGmA mil *mC*mU / Gal3C2 / 3’ (SEQ ID NO: 17242)

[0198] and said antisense nucleotide sequence is:

[0199] TCGACCCCGTCACGCTTCGmG*mU*mCmAmUmGmGmGfUfGfUmCmUmGmUmGmG m GmU*mU*mA / Gal3C2 / 3’. (SEQ ID NO: 17243)

[0200] In a preferred embodiment of the invention said double stranded inhibitory RNA comprises sense and antisense nucleotide sequences linked by a double stranded DNA linker wherein said sense nucleotide sequence is:

[0201] 5’_CGAAGCGTGACCGGGTCGAmC*mC*mAmAmUmUfUfCfCmCmUmGmUmGmGmA mU *mC*mU / Gal3C2 / 3’ (SEQ ID NO: 17244)

[0202] and said antisense nucleotide sequence is:

[0203] 5’TCGACCCGGTCACGCTTCGmG*mU*mCmAmUmGmGmGfUfGfUmCmUmGmUmGm G mGmU*mU*mA / Gal3C2 / 3’. (SEQ ID NO: 17245).

[0204] In a preferred embodiment of the invention said double stranded inhibitory RNA comprises sense and antisense nucleotide sequences linked by a double stranded DNA linker wherein said sense nucleotide sequence is:

[0205] 5’_CGAAGCGCCCTACTCCACTmC*mC*mUmGmGmAmCmAfUfUfCmAmGmAmAmCm AmAmG*mA*mA / Gal3C2 / 3’ (SEQ ID NO: 17246)

[0206] and said antisense nucleotide sequence is: 5’ AGTGGAGTAGGGCGCTTCGmU*mG*mGmGmUmUmAfUfUfUmAfAmAmAmGmA’ mA*mA / Gal3C2 / 3’. (SEQ ID NO: 17247).

[0207] According to a further aspect of the invention there is provided a nucleic acid molecule or a pharmaceutical composition according to the invention for use in the treatment or prevention of a subject that has or is predisposed to hypercholesterolemia.

[0208] In a preferred embodiment of the invention said use is the treatment or prevention of diseases associated with hypercholesterolemia.

[0209] In a preferred embodiment of the invention said disease associated with hypercholesterolemia is selected from the group consisting of: stroke prevention, hyperlipidaemia, cardiovascular disease, atherosclerosis, coronary heart disease, aortic stenosis, cerebrovascular disease, peripheral arterial disease, hypertension, metabolic syndrome, type II diabetes, non-alcoholic fatty acid liver disease, non-alcoholic steatohepatitis, Buerger’s disease, renal artery stenosis, hyper-apobetalipoproteinemia, cerebrovascular atherosclerosis, cerebrovascular disease and venous thrombosis.

[0210] In a preferred embodiment of the invention said nucleic acid molecule is covalently linked to A / -acetylgalactosamine.

[0211] The sugar moiety in N-acetylgalactosamine can comprise glycosidic linkages to improve stability. A variety of glycosidic bonds are known in the art and formed between the hemiacetal of the sugar moiety and several chemical groups forming O-, N-, S- or C- glycosidic bonds. Preferably the N-acetylgalactosamine comprises an O-, N-, S- or C- glycosidic bond.

[0212] In a further embodiment of the invention said N-acetylgalactosamine is linked to either the antisense part of said inhibitory RNA or the sense part of said inhibitory RNA.

[0213] In a further embodiment of the invention said N-acetylgalactosamine is linked to either the antisense strand or the sense strand of said double stranded inhibitory RNA molecule of said first nucleic acid.

[0214] In a further embodiment of the invention said N-acetylgalactosamine is linked to either the antisense strand or the sense strand of said double stranded inhibitory RNA molecule of said second nucleic. In a further embodiment of the invention N-acetylgalactosamine is linked to either the antisense strand or the sense strand of said double stranded inhibitory RNA molecule of said first nucleic acid and is linked to either the antisense strand or the sense strand of said double stranded inhibitory RNA molecule of said second nucleic molecule.

[0215] Preferably, N-acetylgalactosamine is linked to the 3’ terminus is of said sense RNA.

[0216] In an alternative embodiment of the invention N-acetylgalactosamine is linked to the 5’ terminus of said sense RNA.

[0217] In an alternative preferred embodiment of the invention said N-acetylgalactosamine is linked to the 3’ terminus of said antisense RNA.

[0218] In a preferred embodiment of the invention N-acetylgalactosamine is monovalent.

[0219] In a preferred embodiment of the invention N-acetylgalactosamine is divalent.

[0220] In an alternative embodiment of the invention N-acetylgalactosamine is trivalent.

[0221] In a preferred embodiment of the invention said nucleic acid molecule is covalently linked to a molecule comprising the structure:

[0222]

[0223] In an alternative embodiment of the invention said nucleic acid molecule is covalently linked to a molecule comprising the structure:

[0224]

[0225] In an alternative embodiment of the invention said nucleic acid molecule is covalently linked to a molecule comprising the structure:

[0226]

[0227] In an alternative embodiment of the invention said nucleic acid molecule is covalently linked to a molecule comprising the structure:

[0228]

[0229] In an alternative embodiment of the invention said nucleic acid molecule is covalently linked to a molecule comprising the structure:

[0230]

[0231] In an alternative embodiment of the invention said nucleic acid molecule is covalently linked to a molecule comprising the structure:

[0232]

[0233] According to a further aspect of the invention there is provided a medicament comprising a nucleic acid according to the invention.

[0234] According to a further aspect of the invention there is provided a pharmaceutical composition comprising a nucleic acid molecule according to the invention.

[0235] In a preferred embodiment of the invention said composition further includes a pharmaceutical carrier and / or excipient.

[0236] According to a further aspect of the invention there is provided a nucleic acid molecule or a pharmaceutical composition according to the invention for use in the treatment or prevention of a subject that has or is predisposed to hypercholesterolemia.

[0237] In a preferred embodiment of the invention said use is the treatment or prevention of diseases associated with hypercholesterolemia.

[0238] In a preferred embodiment of the invention said disease associated with hypercholesterolemia is selected from the group consisting of: stroke prevention, hyperlipidaemia, cardiovascular disease, atherosclerosis, coronary heart disease, aortic stenosis, cerebrovascular disease, peripheral arterial disease, hypertension, metabolic syndrome, type II diabetes, non-alcoholic fatty acid liver disease, non-alcoholic steatohepatitis, Buerger’s disease, renal artery stenosis, hyper-apobetalipoproteinemia, cerebrovascular atherosclerosis, cerebrovascular disease and venous thrombosis.

[0239] According to an aspect of the invention there is provided a treatment regimen for use in the treatment or prevention of at least one cardiovascular disease comprising administration of a first and second double stranded inhibitory RNA molecule wherein said first double stranded inhibitory RNA molecule is designed with reference to a cardiovascular gene target to be silenced and wherein said second double stranded inhibitory RNA molecule is designed with reference to a different cardiovascular gene target to be silenced wherein said at least first and second double stranded inhibitory RNA molecules are co-administered as simultaneous, sequential, or temporally separate effective dosages to a subject.

[0240] In a preferred embodiment of the invention said first and / or said second double stranded inhibitory RNA molecule comprises modified nucleotides and / or modified sugar(s).

[0241] In a preferred embodiment of the invention said modified nucleotides / sugars are selected from the group: a 3 '-terminal deoxy- thymine (dT) nucleotide, a 2'-0-methyl modified nucleotide, a 2'-fluoro modified nucleotide, a 2'-deoxy-modified nucleotide, a locked nucleotide, an unlocked nucleotide, a conformationally restricted nucleotide, a constrained ethyl nucleotide, an abasic nucleotide, a 2'-amino-modified nucleotide, a 2'-O-allyl-modified nucleotide, 2'-C-alkyl-modified nucleotide, 2' -hydroxyl- modified nucleotide, a 2'-methoxyethyl modified nucleotide, a 2'-0- alkyl-modified nucleotide, a morpholino nucleotide, a phosphoramidate, a non-natural base comprising nucleotide, a tetrahydropyran modified nucleotide, a 1,5-anhydrohexitol modified nucleotide, a cyclohexenyl modified nucleotide, a nucleotide comprising a phosphorothioate group, a nucleotide comprising phosphorodithioate (PS2), a nucleotide comprising a methylphosphonate group, a nucleotide comprising a 5’- phosphate, and a nucleotide comprising a 5 ‘-phosphate mimic, for example a 5’-vinyl phosphate, a nucleotide comprising a 2’-deoxy-2’-fluro and a 2’ methyl sugar base and glycol nucleic acid.

[0242] In a preferred embodiment of the invention said first or and / or second double stranded inhibitory RNA molecule comprises at least one modified nucleotide wherein said modification is 2'-deoxy-2'-fluoro. In a preferred embodiment of the invention said first and / or said second double stranded inhibitory RNA molecule comprises at least one modified nucleotide wherein said modification is 2'-O-methyl.

[0243] In a further preferred embodiment of the invention said first and / or said second double stranded inhibitory RNA molecule comprises at least one phosphorothioate linkage.

[0244] In a further preferred embodiment of the invention said first and / or said second double stranded inhibitory RNA molecule comprises at least one 5'-vinyl phosphate.

[0245] In an embodiment of the invention said first and / or said second double stranded inhibitory RNA molecule comprises at least one modified sugar.

[0246] A sugar modification includes a modified version of the ribosyl moiety, such as -O-modified RNA such as '-O-alkyl or 2'-0-(substituted)alkyl e.g. 2'-0-methyl, T-0-(2-cyanoethyl), 2'-0-(2-methoxy)ethyl (2'-MOE), 2'-0-(2-thiomethyl)ethyl, 2'-0-butyryl, -O-propargyl, 2'-O-allyl, 2'-O-(2-amino)propyl, 2'-O-(2-(dimethylamino)propyl), 2'-O-(2-amino)ethyl, 2'-O-(2-(dimethylamino)ethyl); 2'-deoxy (DNA); 2'-O-(haloalkoxy)methyl, e.g.

[0247] 2'-0-(2-chloroethoxy)methyl (MCEM), -O- (2,2-dichloroethoxy)methyl (DCEM); 2'-<3-alkoxycarbonyl e.g. T-0-[2- (methoxycarbonyl)ethyl] (MOCE), 2'-O-[2-(N-methylcarbamoyl)ethyl] (MCE), T-0-[2-(N,N- dimethylcarbamoyl)ethyl] (DCME); 2'-halo e.g. 2'-F, FANA (2'-F arabinosyl nucleic acid); carbasugar and azasugar modifications; 3 '-O-alkyl e.g. 3'-0-methyl, 3 '-O-butyryl, V-O- propargyl and their derivatives.

[0248] Preferably, said first and / or second double stranded inhibitory RNA molecule is modified and comprises one or more 2-O-methyl moieties.

[0249] In a preferred embodiment of the invention said double stranded inhibitory RNA molecule is modified and comprises one or more 2'-deoxy-2'-fluoro moieties.

[0250] Preferably, said sense nucleotide sequence comprises substantially 2'-O-methyl moieties.

[0251] Preferably, said antisense nucleotide sequence comprises substantially 2'-deoxy-2'-fluoro moieties. In a preferred embodiment of the invention said sense nucleotide sequence is modified wherein said modification pattern comprises the following:

[0252] mmmmmmfffmmmmmmmmmm

[0253] wherein m - 2'-O-methyl and f - 2'-deoxy-2'-fluoro.

[0254] In a preferred embodiment of the invention said antisense nucleotide sequence is modified wherein said modification patter comprises the following:

[0255] mfmfmfmfmfmfmfmfmfm + mUrnll

[0256] wherein m - 2'-O-methyl and f - 2'-deoxy-2'-fluoro.

[0257] In a preferred embodiment of the invention said cardiovascular gene to be silenced is apolipoprotein B (ApoB).

[0258] In a preferred embodiment of the invention said Apo B gene comprises a nucleotide sequence set forth in SEQ ID NO: 12341 wherein said double stranded inhibitory RNA is 19-23 nucleotides in length.

[0259] In a preferred embodiment of the invention said Apo B double stranded inhibitory RNA comprise or consists of a sense nucleotide sequence selected from the group: SEQ ID NO: 12947-13246.

[0260] In a preferred embodiment of the invention said Apo B double stranded inhibitory RNA comprise or consists of an antisense nucleotide sequence selected from the group: SEQ ID NO: 13247-13546.

[0261] In a preferred embodiment of the invention said ApoB double stranded inhibitory RNA comprises a sense nucleotide sequence set forth in SEQ IDs presented in Table 18 wherein said double stranded inhibitory RNA is 19-23 nucleotides in length.

[0262] In a preferred embodiment of the invention said APOB double stranded inhibitory RNA comprises an antisense nucleotide sequence set forth in SEQ IDs presented in Table 18 wherein said double stranded inhibitory RNA is 19-23 nucleotides in length. In a preferred embodiment of the invention said ApoB double stranded inhibitory RNA comprises a sense nucleotide sequence set forth in SEQ IDs presented in Table 19 wherein said double stranded inhibitory RNA is 19-23 nucleotides in length.

[0263] In a preferred embodiment of the invention said APOB double stranded inhibitory RNA comprises an antisense nucleotide sequence set forth in SEQ IDs presented in Table 19 wherein said double stranded inhibitory RNA is 19-23 nucleotides in length.

[0264] In a preferred embodiment of the invention said cardiovascular gene to be silenced is DGAT2.

[0265] In a preferred embodiment of the invention said DGAT2 gene comprises a nucleotide sequence set forth in SEQ ID NO: 12346 wherein said double stranded inhibitory RNA is 19-23 nucleotides in length.

[0266] In a preferred embodiment of the invention said double stranded DGAT2 inhibitory RNA comprise or consists of a sense nucleotide sequence selected from the group: SEQ ID NO: 12348-12646, 17169 and 17171 to 17179.

[0267] In a preferred embodiment of the invention said double stranded DGAT2 inhibitory RNA comprise or consists of an antisense nucleotide sequence selected from the group: SEQ ID NO: 12647-12946, 17170 and 17180 to 17188.

[0268] In a preferred embodiment of the invention said DGAT2 double stranded inhibitory RNA comprises a sense nucleotide sequence set forth in SEQ IDs presented in Table 16 wherein said double stranded inhibitory RNA is 19-23 nucleotides in length.

[0269] In a preferred embodiment of the invention said DGAT2 double stranded inhibitory RNA comprises an antisense nucleotide sequence set forth in SEQ IDs presented in Table 16 wherein said double stranded inhibitory RNA is 19-23 nucleotides in length.

[0270] In a preferred embodiment of the invention said DGAT2 double stranded inhibitory RNA comprises a sense nucleotide sequence set forth in SEQ IDs presented in Table 17 wherein said double stranded inhibitory RNA is 19-23 nucleotides in length. In a preferred embodiment of the invention said DGAT2 double stranded inhibitory RNA comprises an antisense nucleotide sequence set forth in SEQ IDs presented in Table 17 wherein said double stranded inhibitory RNA is 19-23 nucleotides in length.

[0271] In an alternative preferred embodiment of the invention said cardiovascular gene to be silenced is ANGPLT3.

[0272] In a preferred embodiment of the invention said ANGPTL3 gene comprises a nucleotide sequence set forth in SEQ ID NO: 17159 wherein said double stranded inhibitory RNA is 19-23 nucleotides in length.

[0273] In a preferred embodiment of the invention said double stranded ANGPTL 3 inhibitory RNA comprise or consists of a sense nucleotide sequence selected from the group: SEQ ID NO: 15955-16254, 17165 and 17167.

[0274] In a preferred embodiment of the invention said double stranded ANGPTL 3 inhibitory RNA comprise or consists of an antisense nucleotide sequence selected from the group: SEQ ID NO:16255-16554, 17167 and 17168.

[0275] In an alternative preferred embodiment of the invention said cardiovascular gene to be silenced is ANGPLT4.

[0276] In a preferred embodiment of the invention said ANGPTL4 gene comprises a nucleotide sequence set forth in SEQ ID NO: 17160 wherein said double stranded inhibitory RNA is 19-23 nucleotides in length.

[0277] In a preferred embodiment of the invention said ANGPTL4 double stranded inhibitory RNA comprise or consists of a sense nucleotide sequence selected from the group: SEQ ID NO: 16555-16854.

[0278] In a preferred embodiment of the invention said ANGPTL4 double stranded inhibitory RNA comprise or consists of an antisense nucleotide sequence selected from the group: SEQ ID NO: 16855-17154.

[0279] In an alternative preferred embodiment of the invention said cardiovascular gene to be silenced is PCSK9. In a preferred embodiment of the invention said PCSK9 gene comprises a nucleotide sequence set forth in SEQ ID NO: 12342 wherein said double stranded inhibitory RNA is 19-23 nucleotides in length.

[0280] In a preferred embodiment of the invention said double stranded PCSK9 inhibitory RNA comprise or consists of a sense nucleotide sequence selected from the group: SEQ ID NO: 13547-13850 and SEQ ID NO 17161.

[0281] In a preferred embodiment of the invention said double stranded PCSK9 inhibitory RNA comprise or consists of an antisense nucleotide sequence selected from the group: SEQ ID NO: 13851-14154 and 17162.

[0282] In an alternative preferred embodiment of the invention said cardiovascular gene to be silenced is lipoprotein A (LP(a)).

[0283] In a preferred embodiment of the invention said lipoprotein A gene comprises a nucleotide sequence set forth in SEQ ID NO: 12343 wherein said double stranded inhibitory RNA is 19-23 nucleotides in length.

[0284] In a preferred embodiment of the invention said lipoprotein A double stranded inhibitory RNA comprise or consists of a sense nucleotide sequence selected from the group: SEQ ID NO: 14155-14454 and 17163.

[0285] In a preferred embodiment of the invention said lipoprotein A double stranded inhibitory RNA comprise or consists of an antisense nucleotide sequence selected from the group: SEQ ID NO: 14455-14754 and 17164.

[0286] In an alternative preferred embodiment of the invention said cardiovascular gene to be silenced is APOCIII.

[0287] In a preferred embodiment of the invention said Apo Clll gene comprises a nucleotide sequence set forth in SEQ ID NO: 12345 wherein said double stranded inhibitory RNA is 19-23 nucleotides in length.

[0288] In a preferred embodiment of the invention said double stranded ApoCi II inhibitory RNA comprise or consists of a sense nucleotide sequence selected from the group: SEQ ID NO: 15355-15654 and 17200. In a preferred embodiment of the invention said double stranded ApoCi II inhibitory RNA comprise or consists of an antisense nucleotide sequence selected from the group: SEQ ID NO: 15655-15954 and 17199.

[0289] In an alternative preferred embodiment of the invention said cardiovascular gene to be silenced is angiotensinogen.

[0290] In a preferred embodiment of the invention said angiotensinogen gene comprises a nucleotide sequence set forth in SEQ ID NO: 12344 wherein said double stranded inhibitory RNA is 19-23 nucleotides in length.

[0291] In a preferred embodiment of the invention said double stranded angiotensinogen inhibitory RNA comprise or consists of a sense nucleotide sequence selected from the group: SEQ ID NO: 14755-15054.

[0292] In a preferred embodiment of the invention said double stranded angiotensinogen inhibitory RNA comprise or consists of an antisense nucleotide sequence selected from the group: SEQ ID NO: 15055-15354.

[0293] In a preferred embodiment of the invention said nucleic acid molecule is covalently linked to / V-acetylgalactosamine.

[0294] In a preferred embodiment of the invention said first and second double stranded inhibitory RNAs are admixed in a single pharmaceutical composition adapted for administration in said treatment regimen.

[0295] In an alternative embodiment of the invention said first and second double stranded inhibitory RNA are separate compositions adapted for administration in said treatment regimen.

[0296] In a preferred embodiment of the invention said regimen is the treatment or prevention of diseases associated with hypercholesterolemia.

[0297] In a preferred embodiment of the invention said disease associated with hypercholesterolemia is selected from the group consisting of: stroke prevention, hyperlipidaemia, cardiovascular disease, atherosclerosis, coronary heart disease, aortic stenosis, cerebrovascular disease, peripheral arterial disease, hypertension, metabolic syndrome, type II diabetes, non-alcoholic fatty acid liver disease, non-alcoholic steatohepatitis, Buerger’s disease, renal artery stenosis, hyper-apobetalipoproteinemia, cerebrovascular atherosclerosis, cerebrovascular disease and venous thrombosis.

[0298] When administered the compositions of the present invention are administered in pharmaceutically acceptable preparations. Such preparations may routinely contain pharmaceutically acceptable concentrations of salt, buffering agents, preservatives, compatible carriers and optionally other therapeutic agents, such as cholesterol lowering agents, which can be administered separately from the nucleic acid molecule according to the invention or in a combined preparation if a combination is compatible.

[0299] The combination of a nucleic acid according to the invention and the other, different therapeutic agent is administered as simultaneous, sequential, or temporally separate dosages.

[0300] The therapeutics of the invention can be administered by any conventional route, including injection or by gradual infusion over time. The administration may, for example, be oral, intravenous, intraperitoneal, intramuscular, intracavity, subcutaneous, transdermal or transepithelial.

[0301] The compositions of the invention are administered in effective amounts. An “effective amount” is that amount of a composition that alone, or together with further doses, produces the desired response. In the case of treating a disease, such as cardiovascular disease, the desired response is inhibiting or reversing the progression of the disease. This may involve only slowing the progression of the disease temporarily, although more preferably, it involves halting the progression of the disease permanently. This can be monitored by routine methods.

[0302] Such amounts will depend, of course, on the particular condition being treated, the severity of the condition, the individual patient parameters including age, physical condition, size and weight, the duration of the treatment, the nature of concurrent therapy (if any), the specific route of administration and like factors within the knowledge and expertise of the health practitioner. These factors are well known to those of ordinary skill in the art and can be addressed with no more than routine experimentation. It is generally preferred that a maximum dose of the individual components or combinations thereof be used, that is, the highest safe dose according to sound medical judgment. It will be understood by those of ordinary skill in the art, however, that a patient may insist upon a lower dose or tolerable dose for medical reasons, psychological reasons or for virtually any other reasons.

[0303] The pharmaceutical compositions used in the foregoing methods preferably are sterile and contain an effective amount of a nucleic acid molecule according to the invention for producing the desired response in a unit of weight or volume suitable for administration to a patient. The response can, for example, be measured by determining regression of cardiovascular disease and decrease of disease symptoms etc.

[0304] The doses of the nucleic acid molecule according to the invention administered to a subject can be chosen in accordance with different parameters, in particular in accordance with the mode of administration used and the state of the subject. Other factors include the desired period of treatment. If a response in a subject is insufficient at the initial doses applied, higher doses (or effectively higher doses by a different, more localized delivery route) may be employed to the extent that patient tolerance permits. It will be apparent that the method of detection of the nucleic acid according to the invention facilitates the determination of an appropriate dosage for a subject in need of treatment.

[0305] In general, for example, doses of the nucleic acid molecules herein generally will be formulated and administered according to standard procedures. Other protocols for the administration of compositions will be known to one of ordinary skill in the art, in which the dose amount, schedule of injections, sites of injections, mode of administration and the like vary from the foregoing. The administration of compositions to mammals other than humans, (e.g., for testing purposes or veterinary therapeutic purposes), is carried out under substantially the same conditions as described above. A subject, as used herein, is a mammal, preferably a human, and including a nonhuman primate, cow, horse, pig, sheep, goat, dog, cat or rodent.

[0306] When administered, the pharmaceutical preparations of the invention are applied in pharmaceutically acceptable amounts and in pharmaceutically acceptable compositions. The term “pharmaceutically acceptable” means a non-toxic material that does not interfere with the effectiveness of the biological activity of the active ingredients. Such preparations may routinely contain salts, buffering agents, preservatives, compatible carriers, and optionally other therapeutic agents e.g. statins. When used in medicine, the salts should be pharmaceutically acceptable, but non-pharmaceutically acceptable salts may conveniently be used to prepare pharmaceutically acceptable salts thereof and are not excluded from the scope of the invention. Such pharmacologically and pharmaceutically acceptable salts include, but are not limited to, those prepared from the following acids: hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, maleic, acetic, salicylic, citric, formic, malonic, succinic, and the like. Also, pharmaceutically acceptable salts can be prepared as alkaline metal or alkaline earth salts, such as sodium, potassium or calcium salts.

[0307] Compositions may be combined, if desired, with a pharmaceutically acceptable carrier. The term “pharmaceutically acceptable carrier” as used herein means one or more compatible solid or liquid fillers, diluents or encapsulating substances which are suitable for administration into a human. The term “pharmaceutically acceptable carrier” in this context denotes an organic or inorganic ingredient, natural or synthetic, with which the active ingredient is combined to facilitate, for example, solubility and / or stability. The components of the pharmaceutical compositions also are capable of being co-mingled with the molecules of the present invention, and with each other, in a manner such that there is no interaction which would substantially impair the desired pharmaceutical efficacy.

[0308] The pharmaceutical compositions may contain suitable buffering agents, including acetic acid in a salt; citric acid in a salt; boric acid in a salt; and phosphoric acid in a salt. The pharmaceutical compositions also may contain, optionally, suitable preservatives.

[0309] The pharmaceutical compositions may conveniently be presented in unit dosage form and may be prepared by any of the methods well-known in the art of pharmacy. All methods include the step of bringing the active agent into association with a carrier which constitutes one or more accessory ingredients. In general, the compositions are prepared by uniformly and intimately bringing the active compound into association with a liquid carrier, a finely divided solid carrier, or both, and then, if necessary, shaping the product.

[0310] Compositions suitable for parenteral administration conveniently comprise a sterile aqueous or non-aqueous preparation of nucleic acid, which is preferably isotonic with the blood of the recipient. This preparation may be formulated according to known methods using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation also may be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1, 3-butane diol. Among the acceptable solvents that may be employed are water, Ringer’s solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono-or di-glycerides. In addition, fatty acids such as oleic acid may be used in the preparation of injectables. Carrier formulation suitable for oral, subcutaneous, intravenous, intramuscular, etc. administrations can be found in Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, PA.

[0311] According to a further aspect of the invention there is provided a method to treat a subject that has or is predisposed to hypercholesterolemia comprising administering an effective dose of a nucleic acid or a pharmaceutical composition according to the invention thereby treating or preventing hypercholesterolemia.

[0312] In a preferred method of the invention the hypercholesterolemia is familial hypercholesterolemia.

[0313] In a preferred method of the invention there is provided the treatment or prevention of diseases associated with hypercholesterolemia.

[0314] In a preferred method of the invention said disease associated with hypercholesterolemia is selected from the group consisting of: stroke prevention, hyperlipidaemia, cardiovascular disease, atherosclerosis, coronary heart disease, aortic stenosis, cerebrovascular disease, peripheral arterial disease, hypertension, metabolic syndrome, type II diabetes, non-alcoholic fatty acid liver disease, non-alcoholic steatohepatitis, Buerger’s disease, renal artery stenosis, hyper-apobetalipoproteinemia, cerebrovascular atherosclerosis, cerebrovascular disease and venous thrombosis.

[0315] Throughout the description and claims of this specification, the words “comprise” and “contain” and variations of the words, for example “comprising” and “comprises”, means “including but not limited to”, and is not intended to (and does not) exclude other moieties, additives, components, integers or steps. “Consisting essentially” means having the essential integers but including integers which do not materially affect the function of the essential integers.

[0316] Throughout the description and claims of this specification, the singular encompasses the plural unless the context otherwise requires. In particular, where the indefinite article is used, the specification is to be understood as contemplating plurality as well as singularity, unless the context requires otherwise.

[0317] Features, integers, characteristics, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein unless incompatible therewith.

[0318] An embodiment of the invention will now be described by example only and with reference to the following materials, methods, figure, and examples:

[0319] Figure 1. TBE (Tris-borate-EDTA) Polyacrylamide gel (20%) of bi-specific siRNA with various Crook variants (CVO, CV1, CV2, CV3, CV4, CV5, CV6, CV9, CV10) preincubated (+) or not pre-incubated (-) in 80 % Human Serum (HS) for 2 h at 37°C. Mono-specific siRNAs (ApoB_Cr, DGAT2_Acr) were included for reference, and HS only control (no siRNA) also included. Ultra Low Range DNA Ladder used as a size marker;

[0320] Figure 2 A-E (SEQ ID NOs: 17238-17247, 17253-17254, 18434, 18529) are embodiments of APOB / DGAT2 double stranded inhibitory RNAs linked via a DNA linker molecule; and

[0321] Figure 3 (SEQ ID NOs: 18503-18508) are embodiments of DNA linkers according to the invention.

[0322] MATERIALS & METHODS

[0323] Preparation of the siRNA Crook variants for the PAGE

[0324] Duplex siRNA, and bispecific siRNA (Table 1) and its DNA fragment variants (Table 2) were synthesized by CatSci (Cardiff, UK). For serum stability assay, stock siRNAs were incubated in vehicle (nuclease-free water) or in 80 % of human serum (HS) for 2 hours at 37°C. The pre-incubated or freshly prepared siRNAs (100 ng / well) were then mixed with 5 x loading buffer (50 % 10 x TBE, 50 % glycerol) and loaded into 20 % TBE (Tris / Borate / EDTA) Polyacrylamide gel. Serum samples also contained 0.1 % SDS. GeneRuler Ultra Low Range DNA Ladder (Thermo Scientific, SM1211) was used for reference. The PAGE was run for 120 min at 120 V. After the electrophoresis, gel was removed from the cassette and stained with Sybr-Safe (Invitrogen, S33102) in 1 x TBE buffer for 10 min on a gentle shaker and protected from light. The bands on the gel were visualised with SafeVIEW MINI2 LED Transilluminator (Fisherbrand).

[0325] Table 1

[0326] siRNA ID Sense (5’ - 3’) Antisense (3’ - 5’) CGAAGCGCCCTACTCCAC

[0327] mU*mG*mGfGmAfCmCfU TfC*mC*fUmGfGmAfCmAfllf mGfUmAmAmGfUmCfUm PAR_ApoB_Cr UfCmAfGmAfAmCfAmAfGm

[0328] UfGmUfUmC*fU* / VPU / AfA / Gal3C2 / (SEQ ID NO

[0329] (SEQ ID NO 17231) 17223)

[0330] AGTGGAGTAGGGCGCTTC

[0331] mC*fA*mGfUmAfCmCfCm GfG*mU*fCmAfUmGfGmGfU AfCmAfGmAfCmAfCmCfC DGAT2_Acr mGfUmCfUmGfUmGfGmGfU

[0332] mA*fA*mU (SEQ ID NO *mU*fA / Gal3C2 / (SEQ ID NO

[0333] 17233)

[0334] 17232)

[0335] CGAAGCGCCCTACTCCAC

[0336] mU*mG*mGfGmAfCmCfU TfC*mC*fUmGfGmAfCmAfllf mGfUmAmAmGfUmCfUm UfCmAfGmAfAmCfAmAfGm

[0337] PAR_ApoB_ UfGmUfUmC*fU* / VPU / AfA / Gal3C2 / 1(SEQ ID NO

[0338] PAR_ApoB Cr (SEQ ID NO: 17231)

[0339] 17223)

[0340] _Cr- AGTGGAGTAGGGCGCTTC DGAT2_Acr

[0341] GfG*mU*fCmAfUmGfGmGfU mC*fA*mGfUmAfCmCfCm DGAT2_Acr

[0342] mGfUmCfUmGfUmGfGmGfU AfCmAfGmAfCmAfCmCfC *mU*fA / Gal3C2 / 1(SEQ ID mA*fA*mU (SEQ ID NO:

[0343]

[0344] NO 17232) 17233)

[0345] 1AGTGGAGTAGGGCGCTTCG (SEQ ID NO: 17156) (19 nt DNA fragment hybridised with complementary DNA at the 5' end of ApoB and DGAT2)

[0346] * = internucleotide linkage phosphorothioate (PS)

[0347] / VPU / - 5’-Vinyl phosphonate 2’-0Me II

[0348] / Gal3C2 / - N-acetylgalactosamine

[0349] fA, fU, fC, fG = 2’-deoxy-2’-fluro

[0350] mA, mil, mC, mG = 2’ OMe ribonucleotides

[0351] A, T, C, G = DNA bases

[0352]

[0353] Table 2 Sequences of the DNA fragments tested, 5’ to 3’ orientation, with 3’ end attached to the 5’ of the PAR_ApoB_Cr sense strand.

[0354] Sequence ID SEQ ID NOs: Sequence of the 19 nt DNA fragment

[0355] on PAR_ApoB_Cr Sense strand

[0356] CVO 17155 CGAAGCGCCCTACTCCACT

[0357] CV1 18510 CGAAGCGCCCTACT

[0358] CV2 18511 CGAAGCGCCCTACTCCACTCCATC

[0359] CV3 18512 CGAAGGCCCCTACTCCACT

[0360] CV4 18513 CGAAGCGCACGTCAATTCA

[0361] CV5 18514 AGAAGAACATGTAAATTCA

[0362] CV6 CGAAGCGCC

[0363] CV9 17155 CGAAGCGCCCTACTCCACT

[0364]

[0365] CV10 17155 CGAAGCGCCCTACTCCACT Example 1

[0366] PAGE Analysis of Linker Stability

[0367] The stability of DNA linkers (Table 2) connecting bispecific ApoB-DGAT2 siRNAs (Table 1) was investigated by polyacrylamide gel electrophoresis (PAGE) following exposure to (+) or absence of (-) human serum (Figure 1). DNA linker (CVO) showed excellent stability, with ApoB-DGAT2 bispecific remaining intact in the gel. In contrast linker CV1 showed the least stability, with the bispecific separating into single siRNAs. DNA linkers CV2, CV3, CV4, CV5, CV6, CV9 and CV10 showed varying degrees of stability, with both bispecific and single siRNAs evident in the gel.

[0368] Example 2

[0369] Target mRNA Knock-down of ApoB-DGAT2 bispecific siRNA in primary mouse hepatocytes

[0370] As shown in Table 3, ApoB-DGAT2 (CS15 and CS16) bispecific siRNAs showed ApoB KD levels of 64% and 60% respectively at 25 nM and KD levels of 49% and 50% respectively at 4 nM by receptor-mediated uptake in primary mouse hepatocytes. When cells were treated with single siRNA counterpart, CS13, ApoB KD was 72% and 53% respectively at 25nM and 4nM. For DGAT2 target KD, bispecific siRNAs showed KD levels of 76% and 65% at 25nM and 55% and 57% at 4nM. In comparison, single siRNA CS8 led to 76% DGAT2 KD at 25nM and 48% at 4nM.

[0371] These results demonstrate that ApoB-DGAT2 bispecific siRNAs perform as well as single ApoB or DGAT2 siRNAs of the same sequence, in receptor-mediated assays, leading to highly effective silencing of two targets in the same cell. A full description of siRNA structures used can be found in Table 4.

[0372] Table 3. Target mRNA Knock-down (%) in primary mouse hepatocytes by bispecific siRNAs or single siRNA controls, with or without preincubation in 80 % human serum for 2 h at 37°C.

[0373] mRNA KD levels (%)

[0374] Target

[0375] siRNA ID Freshly prepared Pre-incubated in 80% HS gene

[0376] 25n 4nM 1nM 0.1 25n 4nM 1nM 0.1nM M nM M

[0377] PAR ApoB 72 53 37 9 71 60 38 6 CS13 _Apo

[0378] B_Cr

[0379]

[0380] CS8 DGA DGAT2 76 48 25 0 80 67 47 17 T2_A

[0381] cr

[0382] PAR ApoB 64 49 37 10 71 52 31 6 _Apo

[0383] B_Cr

[0384] CS15 DGAT2 76 55 43 6 75 64 48 22 DGA

[0385] T2_A

[0386] cr

[0387] PAR ApoB 60 50 26 3 69 49 31 18 _Apo

[0388] B_Ac

[0389] CS16 r- DGAT2 65 57 32 1 73 58 39 0 DGA

[0390] T2_C

[0391] r

[0392] PAR ApoB 69 61 45 20 66 64 49 2 _Apo

[0393] B

[0394] mTT mTTR 93 91 89 74 94 95 95 77

[0395]

[0396] R

[0397] Example 3

[0398] Stability of ApoB-DGAT2 bispecific siRNA in human serum

[0399] To test stability in human serum, siRNA constructs were preincubated in 80% human serum (HS) for 2 hours at 37C and receptor-mediated uptake assays subsequently performed in primary mouse hepatocytes. Knockdown of target genes was measured after 48hrs by RT-qPCR.

[0400] As shown in Table 3, ApoB-DGAT2 bispecific siRNAs, CS15 and CS16, showed equivalent levels of target KD when compared to single siRNAs of the same sequence, CS13 and CS8. After pre-incubation in 80% human serum, ApoB KD was 71% and 69% respectively for CS15 and CS16 bispecific siRNAs at 25nm and 52% and 49% at 4nM. This level of silencing compares favourably with that shown by single siRNA counterpart CS13; 71% and 60% KD at 25nM and 4nM, respectively. Similarly, levels of DGAT2 KD achieved by bispecific siRNAs was 75% and 73% at 25nM (64% and 58% at 4nM) versus 80% and 67% from single siRNA CS8 at 25nM and 4nM, respectively.

[0401] These results demonstrate that ApoB-DGAT2 bispecific siRNAs are highly stable in 80% human serum and perform as well as single siRNAs of the same sequence in receptor- mediated uptake assays. A full description of siRNA structures used can be found in Table 4. Table 4. ApoB-DGAT2 bispecific siRNAs and single siRNA constructs siR NA ID Sense (5’ - 3’) Antisense (3’ - 5’)

[0402] CGAAGCGCCCTACTCCAC

[0403] mU*mG*mGfGmAfCmCf 7TC*mC*fUmGfGmAfCmAfUf

[0404] PAR_ApoB_ UmGfUmAmAmGfUmCf CS13 UfCmAfGmAfAmCfAmAfGm

[0405] Cr UmUfGmUfUmC*fU* / VP AfA / Gal3C2 / (SEQ ID NO:

[0406] U / (SEQ ID NO: 17231) 17223)

[0407] AGTGGAGTAGGGCGCTTC

[0408] mC*fA*mGfUmAfCmCfC GfG*mU*fCmAfUmGfGmGfU

[0409] m Af C m Af G m AfC m Af C m CS8 DGAT2_Acr mGfUmCfUmGfUmGfGmGfU

[0410] CfCmA*fA*mU (SEQ ID *mU*fA / Gal3C2 / (SEQ ID

[0411] NO: 17233)

[0412] NO: 17232)

[0413] CGAAGCGCCCTACTCCAC

[0414] mU*mG*mGfGmAfCmCf 7TC*mC*fUmGfGmAfCmAfUf UmGfUmAmAmGfUmCf UfCmAfGmAfAmCfAmAfGm UmUfGmUfUmC*fU* / VP AfA / Gal3C2 / 1(SEQ ID NO:

[0415] PAR_ApoB_ U / (SEQ ID NO: 17231)

[0416] 17223)

[0417] CS15 Cr- AGTGGAGTAGGGCGCTTC DGAT2_Acr mC*fA*mGfUmAfCmCfC GfG*mU*fCmAfUmGfGmGfU

[0418] m Af C m Af G m AfC mAf C m mGfUmCfUmGfUmGfGmGfU

[0419] CfCmA*fA*mU (SEQ ID *mU*fA / Gal3C2 / 1(SEQ ID

[0420] NO: 17233)

[0421] NO: 17232)

[0422] AGTGGAGTAGGGCGCTTC

[0423] mU*mG*mGfGmAfCmCf GfC*mC*fUmGfGmAfCmAfUf UmGfUmAmAmGfUmCf UfCmAfGmAfAmCfAmAfGm UmUfGmUfUmC*fU* / VP AfA / Gal3C2 / 1(SEQ ID NO

[0424] PAR_ApoB_ U / (SEQ ID NO: 17231)

[0425] 17222)

[0426] CS16 Acr- CGAAGCGCCCTACTCCAC mC*fA*mGfUmAfCmCfC DGAT2_Cr

[0427] 7TG*mU*fCmAfUmGfGmGfU m Af C m Af G m AfC mAf C m mGfUmCfUmGfUmGfGmGfU CfCmA*fA*mU (SEQ ID *mU*fA / Gal3C2 / 1(SEQ ID NO: 17233)

[0428] NO 17235)

[0429] fC*mC*fUmGfGmAfCmAfUfU mU*mG*mGfGmAfCmCf fCmAfGmAfAmCfAmAfGmAf UmGfUmAmAmGfUmCf PAR_ApoB

[0430] A / Gal3C2 / (SEQ ID NO UmUfGmUfUmC*fU* / VP 17220) U / (SEQ ID NO: 17236) fA*mA*fCmAfGmUfGmUfUfC mU*mU*mUfUmGfUmCf f U m UfGmCf U mCf U m Af U mAf AmCfAmAmGmAfAmCf Mttr

[0431] A / Gal3C2 / (SEQ ID NO GmAfGmAfUmA*fU*mU

[0432]

[0433] 17205) (SEQ ID NO 17237)1AGTGGAGTAGGGCGCTTCG (SEQ ID NO: 17156) (19 nt DNA fragment hybridised with complementary DNA at the 5' end of ApoB and DGAT2)

[0434] * = internucleotide linkage phosphorothioate (PS)

[0435] / VPU / - 5’-Vinyl phosphonate 2’-0Me II

[0436] / Gal3C2 / - N-acetylgalactosamine

[0437] fA, fU, fC, fG = 2’-deoxy-2’-fluro

[0438] mA, mil, mC, mG = 2’ OMe ribonucleotides

[0439] A, T, C, G = DNA bases

[0440]

[0441] Example 4 Comparing in vivo silencing effect of bispecific siRNA (ApoB-DGAT2) to single siRNA controls.

[0442] Mouse study

[0443] Groups of 4 mice for each treatment group were injected subcutaneously (SC) with either vehicle (PBS), or GalNAc-conjugated ApoB-DGAT2 (CS15 or CS16) bispecific, or ApoB (CS13) or DGAT2 (CS8) single siRNA controls (Table 4). Positive siRNA controls included PAR-ApoB and mTTR (Table 4).

[0444] Each compound was administered at either 5mg / kg or 10mg / kg (single siRNAs); equivalent to 10mg / kg and 20mg / kg, respectively, for heterodimer siRNAs. Following sacrifice at either day 5 or day 14, levels of liver target mRNA was measured by RT-qPCR and % knockdown (KD) measured relative to vehicle-treated controls.

[0445] Table 5 shows in vivo silencing of liver target mRNAs (ApoB and DGAT2) by bispecific siRNA compounds (CS15 and CS16) compared to single ApoB or DGAT2 siRNA controls (CS13 and CS8, respectively).

[0446] CS15 bispecific (20mg / kg) led to a 53% KD of both ApoB and DGAT2 mRNA at Day 5, with CS16 bispecific providing 62% and 54% KD of ApoB and DGAT2, respectively. Single siRNAs, CS13 and CS8, at the equivalent dose (10mg / kg) led to 61% and 49% KD of ApoB and DGAT2, respectively. A positive control siRNA (PAR-ApoB; Alnylam) performed similarly, leading to 63% ApoB KD at Day 5. The silencing of ApoB was reduced at Day 14 for bispecific CS15 and single siRNA CS13 (13% and 11%, respectively) which was not unexpected, given the positive control of the same sequence (PAR-ApoB; Alnylam) performed similarly (17% KD). The bispecific CS16 however, provided a KD of 34% at D14.

[0447] In contrast, silencing of DGAT2 mRNA was maintained in mice receiving either bispecific (CS15 67% KD; CS16 57%) or single siRNA CS8 (51%) at Day 14. Importantly, there was a significant increase in silencing of DGAT2 by CS15 bispecific (Day 14) at both doses when compared to single DGAT2 siRNA CS8 (P=0.02 lower dose; P=0.008 higher dose). For CS16 bispecific at the lower dose, ApoB knockdown at Day14 was significantly greater when compared to single ApoB siRNA CS13 (P= 0.04).

[0448] Statistical analysis performed: Two-way Anova and Tukey post-hoc tests.

[0449] These results demonstrate that both ApoB and DGAT2 target KD (%) in vivo by bispecific siRNAs is equivalent or superior to single siRNA controls at both low (5mg / kg) and high dose (10mg / kg), and at both time points (day 5 and day 14). Table 5. Mouse study comparing knock-down (%KD) of liver target mRNA following SC administration of either ApoB-DGAT2 bispecific siRNA or equivalent single ApoB or DGAT2 siRNAs.

[0450] Primer % KD % KD siRNA ID Dose (mg / kg)

[0451] used On day 5 On day 14

[0452] 5 26 7 CS13 PAR_ApoB_Cr ApoB

[0453] 10 61 11 5 33 31 CS8 DGAT2_Acr DGAT2

[0454] 10 49 51 ApoB 10 34 15 PAR_ApoB_Cr- DGAT2 10 41 46 CS15

[0455] DGAT2_Acr ApoB 20 53 13

[0456] DGAT2 20 53 67 ApoB 10 42 20 PAR_ApoB_Acr- DGAT2 10 28 32 CS16

[0457] DGAT2_Cr ApoB 20 62 34

[0458] DGAT2 20 54 57

[0459] 5 44 0 PAR_ApoB ApoB

[0460] 10 63 17

[0461]

[0462] mTTR mTTR 10 91 70

[0463] Table 6 shows Comparative Efficacy (%) of ApoB-DGAT2 bispecific siRNA compared to each single siRNA (ApoB or DGAT2) on day 5 and day 14. [%KD ApoB or DGAT2 by bispecificr siRNA divided by %KD by mono siRNA (x100)].

[0464] Equivalent or superior performance is achieved by bispecific siRNAs compared to single siRNA controls. At the lower dose, for ApoB KD, bispecifics show efficacy of 134 - 164% (Day 5) and 210 - 280% (Day 14) and at higher dose; 87-102% (Day 5) and 114 - 298% (D14). For DGAT2 KD, at the lower dose, comparative efficacy is 84 - 124% (Day 5) and 102 - 147% (Day 14); whereas at higher dose, 109 - 111% (Day 5) and 112 - 131% (Day 14).

[0465] Table 6 Comparative efficacy (%) of ApoB-DGAT2 bispecific siRNAs to single ApoB or DGAT2 siRNAs

[0466] Target Low dose High dose Bispecific

[0467] mRNA Day 5 Day 14 Day 5 Day 14 CS15 ApoB 134 210 87 114 CS16 ApoB 164 280 102 298 CS15 DGAT2 124 147 109 131

[0468]

[0469] CS16 DGAT2 84 102 111 112

[0470] EXAMPLE 5

[0471] Comparing in vitro performance of ApoB-DGAT2 bispecific siRNAs joined by linker variants Primary mouse hepatocytes were plated with the indicated concentrations of APOB- DGAT2 bispecific siRNAs linked by our standard linker or one of three linker variants (Table 7). Cells were incubated with compounds to allow for GalNAc-mediated uptake for 24 hours, media was replaced and cells incubated for a further 24 hours. Cells were then lysed with Cells-to-Ct lysis buffer and relative gene expression measured by TaqMan qPCR, normalising to Gapdh expression and to the average of untreated control cells. No significant differences were identified between the primary linker and linker variants (two-way ANOVA with Sidak’s multiple comparison test).

[0472] Table 7. In vitro knockdown performance of linker variants.

[0473] Apob (relative expression ± Dgat2 (relative expression SD) ± SD)

[0474] 10 Compound 0.1 nM 1 nM 10 nM 0.1 nM 1 nM nM Untreated 1.00 ± 0.05 1.00 ± 0.06

[0475] 0.12 Standard linker

[0476] 0.63 0.40 0.14 0.64 0.37 + (n=3)

[0477] ± 0.09 ± 0.02 ± 0.01 ± 0.08 ± 0.03 0.02

[0478] 0.11 Linker variant 1

[0479] 0.53 0.36 0.14 0.59 0.31 + (n=3)

[0480] ± 0.10 ± 0.05 ± 0.02 ± 0.02 ± 0.07 0.02

[0481] 0.11 Linker variant 2

[0482] 0.59 0.40 0.15 0.57 0.33 + (n=3)

[0483] ± 0.03 ± 0.07 ± 0.02 ± 0.05 ± 0.03 0.03

[0484] 0.12 Linker variant 3

[0485] 0.65 0.35 0.13 0.72 0.35 + (n=3)

[0486] ± 0.02 ± 0.04 ± 0.02 ± 0.09 ± 0.04 0.01

[0487]

[0488] EXAMPLE 6

[0489] Comparing in vivo performance of ApoB-DGAT2 bispecific siRNAs joined by linker variants

[0490] Healthy C57BI6 mice were injected subcutaneously with either RNase-free PBS (Vehicle) or 20 mg / kg of an APOB-DGAT2 bispecific siRNA linked by our standard linker or one of three linker variants; see Figure 3. Seven days after injection mice were sacrificed and livers collected for RNA isolation. Apob and Dgat2 relative expression was measured by TaqMan qPCR, normalised to Gapdh levels within samples and to the average of vehicle treated mice. No significant differences were identified between the primary linker and linker variants (one-way ANOVA with Dunnett’s multiple comparisons test) (Table 8).

[0491] Table 8 In vivo knockdown performance of linker variants.

[0492] Apob (relative Dgat2 (relative Compound expression ± SD) expression ±

[0493] SD) Vehicle (n=8) 1.00 ± 0.09 1.01 ± 0.13 Standard linker (n=8) 0.07 ± 0.01 0.16 ± 0.01 Linker variant 1 (n=4) 0.10 ± 0.02 0.15 ± 0.02 Linker variant 2 (n=4) 0.09 ± 0.01 0.14 ± 0.02 Linker variant 3 (n=4) 0.07 ± 0.01 0.14 ± 0.02

[0494]

[0495] EXAMPLE 7

[0496] In vivo mouse study (Angptl3 -DGAT2 bispecific siRNAs)

[0497] Methodology

[0498] Male C57BL / 6J mice (20-25 g) were group housed in the Saretius animal unit at the University of Reading, and maintained under a 12 h light / dark cycle, at 23°C with humidity controlled according to Home Office regulations.

[0499] Diet

[0500] On arrival mice were given access to standard rodent chow SDS rat expanded diet (RM3-E-FG). On initiation of the study, diet was switched to LBS F3282 mouse high fat diet (HFD) (60% kcal% fat) supplied by LBS, Surrey, UK. Mice were kept on HFD for 6 weeks prior to administration of compounds and for the duration of the study.

[0501] Mice were weighed prior to compound administration (Day 0) and allocated to groups of 12. Groups of 12 mice were then injected subcutaneously with either vehicle (RNase free PBS), control single siRNAs or heterodimer siRNAs (as described below). Mice were then returned to their home cages.

[0502] On Day 7, 21 or 42, four mice from each treatment group of 12 mice were terminally sampled by cardiac puncture under isoflurane. Blood samples and liver tissue were collected immediately as described below.

[0503] For mice culled on Day 7, mice were weighed and assessed for any signs of overt tolerability issues at T=2h and on days 1, 2, 5.

[0504] For mice culled on Day 21, mice were weighed and assessed for any signs of overt tolerability issues on days 9, 14, 16, 21.

[0505] For mice culled on Day 42, mice were weighed and assessed for any signs of overt tolerability issues on days 23, 26, 30, 33, 37, 42.

[0506] Formulation of siRNA compounds

[0507] Bispecific compounds Angptl3-Cr / DGAT2-Acr and DGAT2-Cr / Angptl3-Acr (Table 10 ) were formulated in RNase free PBS to concentrations of 0.8, 2 and 4 mg / mL to provide doses of 4, 10 and 20 mg / kg, respectively, when given subcutaneously in 5 mL / kg dosing volumes.

[0508] Single siRNA control compounds Angptl3-Cr and DGAT2-Acr (Table 10) were each formulated in RNase free PBS to concentrations of 0.4, 1 and 2 mg / mL to provide doses of 2, 5 and 10 mg / kg, respectively, when given subcutaneously in 5 mL / kg dosing volumes. mTTR control siRNA was formulated in RNase free PBS to concentration of 2 mg / mL to provide a dose of 10 mg / kg when given subcutaneously in a 5 mL / kg dosing volume.

[0509] NB: fresh vials of compound were used for each formulation and any remaining material frozen and stored for later measurement of compound analysis (concentration and stability).

[0510] Liver processing for RT-qPCR

[0511] At Day 7, 21 and 42 following siRNA compound or Vehicle injection (n=4), each treatment group was terminally sampled by cardiac puncture under isoflurane. Liver tissue was excised and snap frozen in liquid N2. Total RNA was extracted from homogenates of snap-frozen whole liver using QIAGEN RNeasy Mini Kit (74104).

[0512] Duplex RT-qPCR was performed using the ThermoFisher TaqMan Fast 1-Step Master Mix with TaqMan probes forGAPDH (VIC_PL, Assay Id Mm99999915_g1), mTTR (FAM, Assay Id Mm00443267_m1), Angptl3 (FAM, Assay Id Mm00803820_m1) or DGAT2 (FAM, Assay Id Mm00499536_m1). Relative quantification (RQ) of target mRNA was determined using the AACT method, where GAPDH was used as internal control and the expression changes of the target gene were normalized to the vehicle control.

[0513] Liver histology, one lobe of liver snap frozen in liquid N2 and stored at -20 °C was kept separately for possible histology; staining sections with H&E or oil red O (for detection of fat deposits).

[0514] Blood assays

[0515] Measuring plasma biomarkers; blood samples were taken from 4 mice from each treatment group 7, 21 and 42 days later by cardiac puncture under isoflurane.

[0516] Blood (>300 pL) was placed into Eppendorf tubes on ice containing 6.5 pL EDTA (93 mg / mL). Following gentle mixing, samples were centrifuged at 10,000 rpm x 3 min and plasma (1 x 30 pL for LDL and HDL, 1 x 20 pL for ApoB, 1 x 20 pL for AST and 1 x 20 pL for triglycerides and rest of sample (ANGPTL3), collected into separate Eppendorf tubes on dry ice before storing at -20C (until measured by ELISA).

[0517] Plasma LDL and HDL levels were measured using a CrystalChem mouse LDL assay kit (Cat no # 79980) and CrystalChem mouse HDL assay kit (Cat no # 79990), respectively. Verification of LDL calibration curves were ensured by use of a #79983 mouse LDL control.

[0518] Plasma Triglyceride levels were measured using a Cayman 10010303 kit (Cambridge Bioscience).

[0519] Plasma ApoB levels were measured using an AbCam mouse Apo B ELISA Kit (ab230932).

[0520] AST was measured using an AbCam mouse AST (ab263882) ELISA kit. Plasma Angptl3 levels were measured using an R&D systems, cat. no. MANL30 ELISA kit. Data from Angptl3-DGAT2 Mouse Study

[0521] Groups of 4 mice for each treatment group were injected subcutaneously (SC) with either vehicle (PBS), or GalNAc-conjugated bispecific siRNA (Angptl3-Cr / DGAT2-Acr or DGAT2-Cr / Angptl3-Acr) shown in Table 10. Single siRNA control compounds, Angptl3-Cr and DGAT2-Acr, were included in order to compare levels of target KD with those achieved by bispecific Angptl3-Cr / DGAT2-Acr (Table 9). Compound mTTR was used as a further control for the mouse study. All control compounds were administered to groups of 4 mice.

[0522] Single siRNA compounds (Angptl3-Cr or DGAT2-Acr) were administered at either 2, 5, or 10mg / kg, and bispecific compounds were administered at 4, 10, or 20mg / kg (to ensure equivalent amount of each siRNA).

[0523] Following sacrifice (n=4) at either day 7, 21 or 42, levels of liver target mRNA was measured by RT-qPCR and % knockdown (KD) measured relative to vehicle-treated controls.

[0524] Table 9 shows in vivo silencing of two liver target mRNAs (Angptl3 and DGAT2) by bispecific siRNA compound compared to single siRNA equivalents.

[0525] Bispecific compound (Angptl3-Cr / DGAT2-Acr) showed superior performance at day 7 compared to equivalent single siRNAs. At the lowest dose (4mg / kg), Angptl3-Cr / DGAT2-Acr led to 94.6% and 90.3% KD of Angptl3 and DGAT2 mRNA, respectively, compared to 88.8% and 81.7% KD achieved by Angptl3-Cr and DGAT2-Acr single siRNAs, respectively (2mg / kg).

[0526] At higher doses (10 and 20mg / kg), levels of target mRNA silencing was comparable between bispecific (Angptl3-Cr / DGAT2-Acr) and equivalent single siRNAs (5 and 10mg / kg), with target KD of Angptl3 ( >95%) and that of DGAT2 (90-93%).

[0527] At Day 21 and Day 42 time-points, bispecific (Angptl3-Cr / DGAT2-Acr) sustained high levels of target KD (Angptl3) across all doses (92-97%) comparable to the single equivalent siRNA (Angptl3-Cr) between 92-96% KD. Similarly, target KD of DGAT2 achieved by this heterodimer remained high at Day 21 (although slightly less than at Day7); 87% (lowest dose) and 91.5% (highest dose), while at Day 42, DGAT2 silencing was further slightly reduced to 70% KD (lowest dose) and 89% (highest). Again, these levels of target KD were comparable to the equivalent single siRNA (DGAT2-Acr) at Day 2 Bi Mono1¬(85% - 91.5%) and Day 42 (71.5% - 81%), at equivalent lowest (2mg / kg) and highest doseffiiii speccs speccs (10mg / kg), respectively.

[0528] Bispecific compound (DGAT2-Cr / Angptl3-Acr) also showed high levels of target KD (albeit not as high for DGAT2 KD at the lower dose of 4mg / kg), performing comparably to equivalent single siRNAs. At Day 7, this bispecific led to 92.6% KD (Angptl3) and 74.2% KD (DGAT2) at the lowest dose (4mg / kg); whereas at 10mg / kg and 20mg / kg there was 96% KD (Angptl3) and 92.5% - 94% KD for DGAT2, respectively.

[0529] At Day 21 and Day 42, target silencing was sustained for this bispecific at all doses, achieving >93% KD for Angptl3. For DGAT2; silencing at Day 21 was sustained at 85% KD (4mg / kg), 88% KD (10mg / kg) and 94% (20mg / kg), while at Day 42 there was a slight loss of KD, displaying 78%, 90 and 92%, at respective doses.

[0530] Table 9. Mouse study comparing knock-down (%KD) of liver target mRNA following SC administration of either Angptl3-DGAT2 bispecific siRNA or equivalent single Angptl3 or DGAT2 siRNAs.

[0531] Dose

[0532] %KD Angptl3_Cr DGAT2_Acr mTTR (mg / kg)

[0533] 2 88.8 81.7 - Day 7 5 95.6 90.6 - 10 95.8 93.8 98.5 2 94.3 85.2 - Day 21 5 95.6 87.8 - 10 95.9 91.5 95.3 2 92.2 71.5

[0534] Day 42 5 95.4 86.5

[0535] 10 96.2 88.1 35.6 Angp tl3_Cr- DGAT2_Cr- Dose DGA1 F2_Acr Angptl3_Acr

[0536] (mg / kg) Target Angptl3 DGAT2 Angptl3 DGAT2

[0537] mRNA 4 94.6 90.3 92.6 74.2

[0538] Day 7 10 96.5 92.3 95.9 92.5

[0539] 20 97.2 93.2 95.6 94.0

[0540] 4 95.3 87.2 95.1 85.0

[0541] Day 21 10 94.6 84.4 95.9 88.1

[0542] 20 96.8 91.5 96.9 94.0

[0543] 4 92.3 69.6 93.5 77.8

[0544] Day 42 10 95.9 86.2 95.9 89.6

[0545]

[0546] 20 96.8 88.9 96.8 92.3

[0547] Table 10 Single siRNA controls

[0548] Single SENSE STRAND (5’ -3’) ANTISENSE STRAND siRNA (5’-3’)

[0549] controls

[0550] Angptl3-Cr CGAAGCGCCCTACTCCACT*(invAb)*mGm mU*fA*mC*fUmGfAmU CmUmCmAmAmCmAfUfAfUmUmUmGmAm fCmAfAmAfUmAfUmGf UmCmAmGmUmA* / invAb / * / Gal3C2 / (SEQ UmUfGmAfG*Mc (SEQ ID NO: 17248) ID NO: 17252) DGAT2-Acr AGTGGAGTAGGGCGCTTCGmU*mG*mGm / VPU / *fU*mUmCmUfU GmUmUmAfUfUfUmAfAmAmAmGmA*mA*m mUmUmAmAmAmUm A / Gal3C2 / (SEQ ID NO: 17247) A*fA*mC*fC*mC*mA*m C*fA (SEQ ID NO:

[0551] 18529)

[0552] 2 Heterodimer siRNAs: ANGPTL3-DGAT2

[0553] ANGPTL3- ANGPTL3-Cr

[0554] Cr / DGAT2- CGAAGCGCCCTACTCCACT*(invAb)*mGm mU*fA*mC*fUmGfAmU Acr CmUmCmAmAmCmAfUfAfUmUmUmGmAm fCmAfAmAfUmAfUmGf UmCmAmGmUmA* / invAb / * / Gal3C2 / (SEQ UmUfGmAfG*mC ID NO: 17248) (SEQ ID NO: 17252) DGAT2-Acr

[0555] AGTGGAGTAGGGCGCTTCGmU*mG*mGm / VPU / *fU*mUmCmUfU GmUmUmAfUfUfUmAfAmAmAmGmA*mA*m mUmUmAmAmAmUm A / Gal3C2 / (SEQ ID NO: 17247) A*fA*mC*fC*mC*mA*m C*fA (SEQ ID NO:

[0556] 18529)

[0557] DGAT2- DGAT2-Cr / VPU / *fU*mUmCmUfU Cr / ANGPT CGAAGCGCCCTACTCCACTmU*mG*mGm mUmUmAmAmAmUm L3-Acr GmUmUmAfUfUfUmAfAmAmAmGmA*mA*m A*fA*mC*fC*mC*mA*m A / Gal3C2 / (SEQ ID NO: 17250) C*fA (SEQ ID NO:

[0558] 18529)

[0559] ANGPTL3-Acr

[0560] AGTGGAGTAGGGCGCTTCG*(invAb)*mGm mU*fA*mC*fUmGfAmU CmUmCmAmAmCmAfUfAfUmUmUmGmAm fCmAfAmAfUmAfUmGf UmCmAmGmUmA* / invAb / * / Gal3C2 / (SEQ UmUfGmAfG*mC ID NO: 17251) (SEQ ID NO: 17252)

[0561]

[0562] fA, fll, fC, fG = 2’-F ribonucleotides

[0563] mA, mil, mC, mG = 2’ OMe ribonucleotides

[0564] / VPU / = 5’-Vinyl phosphonate 2’-OMe II

[0565] ZinvAb / = inverted abasic deoxyribose

[0566] * = internucleotide linkage phosphorothioate (PS)

[0567] A, T, C, G = DNA bases

[0568] Bispecific siRNAs formed by hybridising crook with complementary anticrook to form DNA linker

[0569] Crook = 19nt single stranded DNA (5’-3’) CGAAGCGCCCTACTCCACT(SEQ ID NO 17155) Anticrook = 19nt single stranded DNA (5’-3’) AGTGGAGTAGGGCGCTTCG (SEQ ID NO 17156)

[0570] Table 11

[0571] SEQ ID NO Description

[0572] 12341 ApoB

[0573] 12342 PCSK9

[0574] 12343 Lp(a)

[0575] 12344 Angiotensinogen

[0576] 12345 APOCIII

[0577] 12346 DGAT2

[0578] 12348-12646 DGAT2 sense

[0579] 12647 to 12946 DGAT2 antisense

[0580] 12947 to 13246 ApoB sense

[0581] 13247-13546 ApoB antisense

[0582] 13547-13850 PCSK9 sense

[0583] 13851-14154 PCSK9 antisense

[0584] 14155-14454 Lp(a) sense

[0585] 14455-14754 Lp(a) antisense

[0586] 14755-15054 Angiotensinogen sense

[0587] 15055-15354 Angiotensinogen antisense

[0588] 15355-15654 APOCIII sense

[0589] 15655-15954 APOCIII antisense

[0590] 15955-16254 ANGPTL3 sense

[0591] 16255-16554 ANGPTL3 antisense

[0592] 16555-16854 ANGPTL4 sense

[0593] 16855-17154 ANGPTL4 antisense

[0594] 17155 Single stranded DNA

[0595] 17156 Single stranded DNA

[0596] 17157 Single stranded DNA

[0597]

[0598] 17158 Single stranded DNA

[0599] 17159 ANGPTL3

[0600] 17160 ANGPTL4

[0601] 17161 PCSK9 sense

[0602] 17162 PCSK9 antisense

[0603] 17163 Lp(a) sense

[0604] 17164 Lp(a) antisense

[0605] 17165 ANGPTL3 sense

[0606] 17166 ANGPTL3 antisense

[0607] 17167 ANGPTL3 sense

[0608] 17168 ANGPTL3 antisense

[0609] 17169 DGAT2 sense

[0610] 17170 DGAT2 antisense

[0611] 17171-17179 DGAT2 sense

[0612] 17180-17188 DGAT2 antisense

[0613] 17189-17190 PCSK9 sense crook and anticrook

[0614] 17191-17192 Lp(a) sense crook and anticrook

[0615] 17193-17194 ANGPTL3 sense crook and anticrook

[0616] 17195-17196 ANGPTL3 sense crook and anticrook

[0617] 17197-17198 DGAT 2 sense crook and anticrook

[0618] 17199 APOCI 11 antisense

[0619] 17200 APOCI 11 sense

[0620] 17201-17202 APOCI 11 crook and anticrook

[0621]

[0622] Table 12

[0623] ApoB sequence screen in HepG2 cells.

[0624] HepG2 cells were transfected with the indicated concentration of siRNAs, using RNAiMAX lipofectamine, in triplicate. 48-hours after transfection cells were lysed and RT-qPCR performed to measure the relative expression level of APOB, normalised to GAPDH gene expression levels. Relative knockdown of APOB was calculated against cells treated with RNAiMAX and no siRNA.

[0625] Ove 0.1 10 SEQ SEQ ID

[0626] rail Sequ nM 1 nM

[0627] ran ence KD nM ID NOs: Antisense

[0628] ID KD KD NOs: Sense (5’-3’) (5’-3’) k (%) (%) (%)

[0629] APOB 18435 CCCTCAACTTT AGUUUAGAAAA 1 64 75 84 57 TCTAAACT 18455 GUUGAGGG

[0630] 18436 2 APOB 64 74 78 GTCCCAGGTAU UUUCGAAUAUA 18456

[0631]

[0632] _22 ATTCGAAA CCUGGGAC 3 APOB

[0633] 23 59 72 78 18437 GUUCCAUGUC UGUAAAUGGGA CCAUUUACA 18457 CAUGGAAC 4 APOB

[0634] 21 61 73 75 18438 GCACGUGGGU UAAUUUGGAAC UCCAAAUUA 18458 CCACGUGC 5 APOB

[0635] 40 60 73 75 18439 CAAGGGUGUU UAUGGAAAUAA AUUUCCAUA 18459 CACCCUUG 6 APOB

[0636] 53 60 69 77 18440 CUCAAGACCCA UGUUAAAUUGG AUUUAACA 18460 GUCUUGAG 8 APOB

[0637] 24 63 70 74 18441 GUACUGUCCCA AAUAUACCUGG GGUAUAUU 18461 GACAGUAC 7 APOB

[0638] 25 57 70 77 18442 CCAAUUUCCCU AGAUCCACAGG GUGGAUCU 18462 GAAAUUGG 9 APOB

[0639] 59 56 72 76 18443 GGGUUCCAAAU AACUAUUAAUU UAAUAGUU 18463 UGGAACCC 10 APOB

[0640] 32 47 69 80 18444 CAGGAAGGGC AUUCUUUGAGC UCAAAGAAU 18464 CCUUCCUG 11 APOB

[0641] 5 61 69 72 18445 GGGAACUGUU AAAUCUUUCAA GAAAGAUUU 18465 CAGUUCCC 12 APOB

[0642] 47 60 67 77 18446 GAAACAACCCA UUUGAGACUGG GUCUCAAA 18466 GUUGUUUC 13 APOB

[0643] 11 53 69 79 18447 CCCAUGGUCU UUUAACUCAAG UGAGUUAAA 18467 ACCAUGGG 14 APOB

[0644] 58 50 67 79 18448 CAAAGUUAAUU UUCUUCCCAAU GGGAAGAA 18468 UAACUUUG 16 APOB

[0645] 31 58 69 72 18449 CCCUAUUCUCU UAGUUACCAGA GGUAACUA 18469 GAAUAGGG 15 APOB

[0646] 15 55 69 76 18450 CAAUGAAGGGA UUUCAAAUUCC AUUUGAAA 18470 CUUCAUUG 17 APOB

[0647] 1 60 68 69 18451 CCCUGAAGUU UAACACAUCAA GAUGUGUUA 18471 CUUCAGGG 18 APOB

[0648] 56 52 67 78 18452 GAGGGUAGUC UACUGUUAUGA AUAACAGUA 18472 CUACCCUC 19 APOB

[0649] 46 54 57 78 18453 CACUAAAUUCC AGACCAUGGGA CAUGGUCU 18473 AUUUAGUG 20 APOB

[0650]

[0651] _13 39 63 78 18454 GUACUGGGUU UUGACCAUUAA AAUGGUCAA 18474 CCCAGUAC Sense modification pattern - mmmmmmfffmmmmmmmmmm

[0652] Antisense modification pattern - mfmfmfmfmfmfmfmfmfm + mUrnll

[0653] m - 2'-0-methyl; f - 2'-fluoro; KD - knockdown

[0654] Table 13 ApoB sequence screen in primary NHP hepatocytes. Primary NHP (cynomolgus monkey) hepatocytes were transfected with the indicated concentration of siRNAs, using RNAiMAX lipofectamine, in triplicate. 48-hours after transfection cells were lysed and RT-qPCR performed to measure the relative expression level of APOB, normalised to GAPDH gene expression levels. Relative knockdown of APOB was calculated against cells treated with RNAiMAX and no siRNA. Ov SEQ SEQ ID Seq 10 1 0.1

[0655] er ID NOs:

[0656] uen nM nM nM Antisense all NOs: Sense (5’-3’)

[0657] ce KD KD KD (5’-3’) ra

[0658] ID (%) (%) (%)

[0659] nk

[0660] AP 18475 18489 AGUUUAGA CCCUCAACUUUUC

[0661] 1 OB_ 98 98 95 AAAGUUGA UAAACU

[0662] 57 GGG AP 18476 18490 UUUGAGAC GAAACAACCCAGU

[0663] 2 OB_ 97 98 96 UGGGUUGU CUCAAA

[0664] 47 UUC AP 18477 18491 UGUUAAAU CUCAAGACCCAAU

[0665] 3 OB_ 97 97 94 UGGGUCUU UUAACA

[0666] 53 GAG AP 18478 18492 AGAUCCAC CCAAUUUCCCUGU

[0667] 4 OB_ 97 96 86 AGGGAAAU GGAUCU

[0668] 25 UGG AP 18479 18493 AACUAUUA GGGUUCCAAAUUA

[0669] 5 OB_ 96 97 91 AUUUGGAA AUAGUU

[0670] 59 CCC AP 18480 18494 UAAUUUGG GCACGUGGGUUC

[0671] 6 OB_ 96 96 91 AACCCACG CAAAUUA

[0672] 21 UGC AP 18481 18495 UUUAACUC CCCAUGGUCUUGA

[0673] 7 OB_ 96 95 84 AAGACCAU GUUAAA

[0674] 11 GGG AP 18482 18496 UGUAAAUG GUUCCAUGUCCCA

[0675] 8 OB_ 95 94 92 GGACAUGG UUUACA

[0676] 23 AAC AP 18483 18497 UUCUUCCC CAAAGUUAAUUGG

[0677] 9 OB_ 97 95 74 AAUUAACU GAAGAA

[0678] 58 UUG AP 18484 18498 AUUCUUUG CAGGAAGGGCUCA

[0679] 10 OB_ 94 95 89 AGCCCUUC AAGAAU

[0680] 32 CUG AP 18485 18499 AAUAUACC GUACUGUCCCAGG

[0681] 11 OB_ 93 91 78 UGGGACAG UAUAUU

[0682] 24 UAC AP 18486 18500 UUUCGAAU GUCCCAGGUAUAU

[0683] 12 OB_ 94 88 75 AUACCUGG UCGAAA

[0684] 22 GAC AP 18487 18501 UAUGGAAA CAAGGGUGUUAUU

[0685] 13 OB_ 41 28 10 UAACACCC UCCAUA

[0686] 40 UUG AP 18488 18502 AAAUCUUU GGGAACUGUUGAA

[0687] 14 OB_ 12 4 -7 CAACAGUU

[0688] AGAUUU

[0689]

[0690] 5 CCC Sense modification pattern - mmmmmmfffmmmmmmmmmm

[0691] Antisense modification pattern - mfmfmfmfmfmfmfmfmfmfm + mUrnll

[0692] m - 2'-0-methyl; f - 2'-fluoro; KD - knockdown Table 14 ApoB-DGAT2 Bispecific siRNAs and single siRNA constructs

[0693] Sequence ID Sequence (5’-3’)

[0694] CGAAGCGCCCTACTCCACTmC*mC*mAmAmUmUfUfCfC Crook-ApoB_25 Sense mCmUmGmUmGmGmAmU*mC*mU / Gal3C2 / (SEQ ID NO:

[0695] 17238) CGAAGCGTAGCCGGGGGAAmC*mC*mAmAmUmUfUfCfC Crook2-ApoB_25 Sense mCmUmGmUmGmGmAmU*mC*mU / Gal3C2 / (SEQ ID NO:

[0696] 17240) CGAAGCGTGACGGGGTCGAmC*mC*mAmAmUmUfUfCfC Crook3-ApoB_25 Sense mCmUmGmUmGmGmAmU*mC*mU / Gal3C2 / (SEQ ID NO:

[0697] 17242) CGAAGCGTGACCGGGTCGAmC*mC*mAmAmUmUfUfCfC Crook4-ApoB_25 Sense mCmUmGmUmGmGmAmU*mC*mU / Gal3C2 / (SEQ ID NO:

[0698] 17244)

[0699] mA*fG*mAfU mCfC mAfCmAfGmGfG mAfAmAfU mUfG mG*m ApoB_25 Antisense

[0700] U*mU (SEQ ID NO: 17253) AGTGGAGTAGGGCGCTTCGmG*mU*mCmAmUmGmGmG Anticrook-DGAT2_09 Sense fUfGfUmCmUmGmUmGmGmGmU*mU*mA / Gal3C2 / (SEQ ID NO: 17239) TTCCCCCGGCTACGCTTCGmG*mU*mCmAmUmGmGmGf Anticrook2-DGAT2_09 Sense UfGfUmCmUmGmUmGmGmGmU*mU*mA / Gal3C2 / (SEQ ID NO: 17241) TCGACCCCGTCACGCTTCGmG*mU*mCmAmUmGmGmGf Anticrook3-DGAT2_09 Sense UfGfUmCmUmGmUmGmGmGmU*mU*mA / Gal3C2 / (SEQ ID NO: 17243) TCGACCCGGTCACGCTTCGmG*mU*mCmAmUmGmGmG Anticrook4-DGAT2_09 Sense fUfGfUmCmUmGmUmGmGmGmU*mU*mA / Gal3C2 / (SEQ ID NO: 17245) mU*fA*mAfCmCfCmAfCmAfGmAfCmAfCmCfCmAfUmG*fA* DGAT2_09 Antisense

[0701] mC (SEQ ID NO: 17254)

[0702] Crook-ApoB_25 Mono Crook-ApoB_25 Sense + ApoB_25 Antisense Crook2-ApoB_25 Mono Crook2-ApoB_25 Sense + ApoB_25 Antisense Crook3-ApoB_25 Mono Crook3-ApoB_25 Sense + ApoB_25 Antisense Crook4-ApoB_25 Mono Crook4-ApoB_25 Sense + ApoB_25 Antisense

[0703] Anticrook-DGAT2_09 Mono Anticrook-DGAT2_09 Sense + DGAT2_09 Antisense Anticrook2-DGAT2_09 Mono Anticrook2-DGAT2_09 Sense + DGAT2_09 Antisense Anticrook3-DGAT2_09 Mono Anticrook3-DGAT2_09 Sense + DGAT2_09 Antisense Anticrook4-DGAT2_09 Mono Anticrook4-DGAT2_09 Sense + DGAT2_09 Antisense

[0704] Bispecific 1 Crook-ApoB_25 Mono + Anticrook-DGAT2_09 Mono Bispecific 2 Crook2- ApoB_25 Mono + Anticrook2-DGAT2_09 Mono Bispecific 3 Crook3- ApoB_25 Mono + Anticrook3-DGAT2_09 Mono

[0705]

[0706] Bispecific 4 Crook4- ApoB_25 Mono + Anticrook4-DGAT2_09 Mono

[0707] fA, fll, fC, fG = 2’-F ribonucleotides

[0708] mA, mil, mC, mG = 2’ OMe ribonucleotides

[0709] A, T, C, G = DNA bases * = internucleotide linkage phosphorothioate (PS)

[0710] / Gal3C2 / = GalNAc

[0711] Bispecific siRNAs formed by hybridising crook with complementary anticrook to form DNA linker

[0712] Table 15 Control ApoB-DGAT2 Bispecific siRNAs and single siRNA constructs

[0713] Sequence ID Sequence (5’-3’)

[0714] CGAAGCGCCCTACTCCACTmC*mC*mUmGmGmAmC Crook-PAR_APOB Sense mAfUfUfCmAmGmAmAmCmAmAmG*mA*mA / Gal3C2 /

[0715] (SEQ ID NO: 17246) / VPU / *fU*mCfUmUfGmUfUmCfUmGfAmAfUmGfUmCfC PAR_APOB Antisense

[0716] mAfGmG*mG*mU (SEQ ID NO: 17255) AGTGGAGTAGGGCGCTTCGmU*mG*mGmGmUmUm Anticrook-DGAT2_1473

[0717] AfUfUfUmAfAmAmAmGmA*mA*mA / Gal3C2 / (SEQ I D Sense

[0718] NO: 17247) / VPU / *fU*mUmCmUfUmUmUmAmAmAmUmA*fA*mC*f DGAT2_1473 Antisense

[0719] C*mC*mA*mC*fA (SEQ ID NO: 18529)

[0720] Crook-PAR_APOB Mono Crook-PAR_APOB Sense + PAR_APOB Antisense Anticrook-DGAT2_1473 Sense + DGAT2_1473 Anticrook-DGAT2_1473 Mono

[0721] Antisense

[0722] Crook-PAR_APOB Mono + Anticrook-DGAT2_1473 Bispecific 5

[0723]

[0724] Mono

[0725] fA, fll, fC, fG = 2’-F ribonucleotides

[0726] mA, mil, mC, mG = 2’ OMe ribonucleotides

[0727] A, T, C, G = DNA bases

[0728] / VPU / = 5’-Vinyl phosphonate 2’-OMe U

[0729] * = internucleotide linkage phosphorothioate (PS)

[0730] / Gal3C2 / = GalNAc

[0731] Bispecific siRNAs formed by hybridising crook with complementary anticrook to form DNA linker

[0732] Table 16: selected DGAT2 sense and antisense nucleotide sequences

[0733] ID SEQ Sense DGAT2 SEQ ID Antisense DGAT2 ID NOs:

[0734] NOs:

[0735] DGAT- 18521 UGGGUUAUUUAAAAGAAA 18522 UUU CUUUUAAAUAAC C CA 1473

[0736] DGAT2 1 12347 CU GUAAAUUU GGAAGU GU C 12647 GACACUU C CAAAUUUACAG DGAT2_2 12348 CCAUGAGCUAGGUGGAGUA 12648 UACUCCACCUAGCUCAUGG DGAT2 3 12349 C GAG CAGGAACUAUAU CUU 12649 AAGAUAUAGUUCCUGGUGG DGAT2 4 12350 U C CAGAAAUACAUU GGUUU 12650 AAAC CAAU GUAUUU CU GGA DGAT2 5 12351 CCGCAAGGGCUUUGUGAAA 12651 UUUCACAAAGCCCUUGCGG DGAT2_6 12352 GCAAGAAGUUCCCAGGCAU 12652 AUGCCUGGGAACUUCUUGC DGAT2 7 12353 CAUGGGUGUCUGUGGGUUA 12653 U AAC C C AC AGAC AC C C AU G DGAT2_8 12354 U CU GUAAAUUU GGAAGU GU 12654 ACACUU C CAAAUUUACAGA

[0737]

[0738] DGAT2_9 12355 UU G GAGAGAAU GAAGU GU A 12655 UACACUU CAUU CU CU C CAA DGAT2 10 12356 C CAGUUAGAU GAUU CACUU 12656 AAGU GAAU CAU CUAACU GG DGAT2 11 12357 CGAUGGGUCCAGAAGAAGU 12657 ACUUCUUCUGGACCCAUCG DGAT2 12 12358 GCAGCAGAUUAGUUCCAAA 12658 UUUGGAACUAAUCUGCUGC DGAT2 13 12359 GUCUGUGGGUUAUUUAAAA 12659 UUUUAAAUAAC C CACAGAC DGAT2 14 12360 UCACUUGGCUGGUGUUUGA 12660 U C AAAC AC C AG C C AAGU GA DGAT2 15 12361 C CUUU GGAGAGAAU GAAGU 12661 ACUU CAUU CU CU C CAAAGG DGAT2 16 12362 C GAU CCU CAU GUACAUAUU 12662 AAUAUGUACAUGAGGAUGG DGAT2 17 12363 GCAAGGGCUUUGUGAAACU 12663 AGUUUCACAAAGCCCUUGC DGAT2 18 12364 GCGAAAGCCACUUCUCAUA 12664 UAUGAGAAGUGGCUUUCGC DGAT2 19 12365 CAAGAAGUUCCCAGGCAUA 12665 UAUGCCUGGGAACUUCUUG DGAT2 20 12366 UGUACAAGCAGGUGAUCUU 12666 AAGAU CAC CU GCUU GUACA DGAT2 21 12367 UGUUCUAGGUGGUGGCUAA 12667 UUAGC CAC CAC CUAGAACA DGAT2 22 12368 U GGAC CAGUUAGAU GAUU C 12668 GAAU CAU CUAACU GGU C CA DGAT2 23 12369 CU GAC CAC CAGGAACUAUA 12669 UAUAGUUCCUGGUGGUCAG DGAT2 24 12370 GCUCUGUAAAUUUGGAAGU 12670 ACUU C CAAAUUUACAGAGC DGAT2 25 12371 GAUGGGUCCAGAAGAAGUU 12671 AACUUCUUCUGGACCCAUC DGAT2 26 12372 U G GAGAGAAU GAAGU GU AC 12672 GUACACUU CAUU CU CU C CA DGAT2 27 12373 GCAC CAU GU CAGACUUUU G 12673 CAAAAGUCUGACAUGGUGC DGAT2 28 12374 GCGCUACUUUCGAGACUAC 12674 GUAGUCUCGAAAGUAGCGC DGAT2 29 12375 C CAUUAGU GACUU GGAC CA 12675 UGGUCCAAGUCACUAAUGG DGAT2 30 12376 GU CUAGU CCU GAAACU GCA 12676 UGCAGUUUCAGGACUAGAC DGAT2 31 12377 CUGUGGGUUAUUUAAAAGA 12677 U CUUUUAAAUAAC C CACAG DGAT2 32 12378 CUUGGGUGGCUGAUGACAU 12678 AU GU CAU C AG C C AC C C AAG DGAT2 33 12379 UGCCUGUGUUGAGGGAGUA 12679 UACUCCCUCAACACAGGCA DGAT2 34 12380 UGUCUGUGGGUUAUUUAAA 12680 UUUAAAUAAC C CACAGACA DGAT2 35 12381 UU C CAGAAAUACAUU GGUU 12681 AAC CAAU GUAUUU CU GGAA DGAT2 36 12382 UGAGCUAGGUGGAGUAACU 12682 AGUUACU C CAC CUAGCU CA DGAT2 37 12383 UACAUAUU CU GCACU GAUU 12683 AAU C AGU G C AGAAU AU GU A DGAT2 38 12384 GAAGU GAG C AAGAAGUU C C 12684 GGAACUUCUUGCUCACUUC DGAT2 39 12385 GGUGUCUGUGGGUUAUUUA 12685 U AAAU AAC C C AC AGAC AC C DGAT2 40 12386 UCAUGGAGCUGACCUGGUU 12686 AACCAGGUCAGCUCCAUGA DGAT2 41 12387 CUGAGCAGCAGAUUAGUUC 12687 GAACUAAUCUGCUGCUCAG DGAT2 42 12388 GGUCUAGGCUGUUUCUCUC 12688 GAGAGAAAC AG C CU AGAC C DGAT2 43 12389 CAGAUUAGUU C CAAAGCAG 12689 CUGCUUUGGAACUAAUCUG DGAT2 44 12390 CGCAAGGGCUUUGUGAAAC 12690 GUUUCACAAAGCCCUUGCG DGAT2 45 12391 CCAGGAACUAUAUCUUUGG 12691 C CAAAGAUAUAGUU C CU GG DGAT2 46 12392 GAAGUGUACAAGCAGGUGA 12692 U CAC CU GCUU GUACACUU C DGAT2 47 12393 U C CU CAU GUACAUAUU CU G 12693 C AGAAU AU GU AC AU GAG GA DGAT2 48 12394 C GU CUAGU CCU GAAACU GC 12694 GCAGUUUCAGGACUAGACG DGAT2 49 12395 GGACCAGUUUCUCUGCCAA 12695 UUGGCAGAGAAACUGGUCC DGAT2_50 12396 GGGUGUCUGUGGGUUAUUU 12696 AAAU AAC C CAC AGAC AC C C DGAT2_51 12397 GGAACACACCCAAGAAAGG 12697 CCUUUCUUGGGUGUGUUCC DGAT2_52 12398 C CAU GU CAGACUUUU GUAU 12698 AU AC AAAAGU CU GAC AU G G

[0739]

[0740] DGAT2_53 12399 CAAAGGAAACU CAGU CUU C 12699 GAAGACUGAGUUUCCUUUG DGAT2_54 12400 UUCUGUUAUCUCUUGAUGA 12700 U CAU C AAGAGAU AAC AGAA DGAT2_55 12401 GUGUCUGUGGGUUAUUUAA 12701 UUAAAUAAC C CACAGACAC DGAT2_56 12402 GAU GU CAGACUUUU GUAUA 12702 UAUACAAAAGU CU GACAU G DGAT2_57 12403 UCGCUGUGCUCUACUUCAC 12703 GUGAAGUAGAGCACAGCGA DGAT2_58 12404 UGGCAAUGCUAUCAUCAUC 12704 GAUGAUGAUAGCAUUGCCA DGAT2_59 12405 UCAAAGAAUGGGAGUGGCA 12705 UGCCACUCCCAUUCUUUGA DGAT2_60 12406 GGGUCCAGAAGAAGUUCCA 12706 UGGAACUUCUUCUGGACCC DGAT2_61 12407 UCAUGGGUGUCUGUGGGUU 12707 AAC C C AC AGAC AC C CAU GA DGAT2_62 12408 CU G GAAC AC AC C C AAGAAA 12708 UUUCUUGGGUGUGUUCCAG DGAT2_63 12409 GCUACUUU C GAGACUACUU 12709 AAGUAGUCUC GAAAGU AG C DGAT2_64 12410 GCAGUGCCAUCCUCAUGUA 12710 UACAUGAGGAUGGCACUGC DGAT2_65 12411 UUGCUCUGUAAAUUUGGAA 12711 UU C CAAAUUUACAGAGCAA DGAT2_66 12412 G GAGAGAAU GAAGU GU AC A 12712 U GUACACUU CAUU CU CU C C DGAT2_67 12413 UUCCCAUCCAGCUGGUGAA 12713 UUCACCAGCUGGAUGGGAA DGAT2_68 12414 GUUCUAGGUGGUGGCUAAA 12714 UUUAGC CAC CAC CUAGAAC DGAT2_69 12415 CUAGGUGGAGUAACUGGUU 12715 AAC CAGUUACU C CAC CUAG DGAT2 70 12416 CUACUUU C GAGACUACUUU 12716 AAAGUAGU CU C GAAAGU AG DGAT2 71 12417 GGCGAAAGCCACUUCUCAU 12717 AUGAGAAGUGGCUUUCGCC DGAT2 72 12418 CUAGGGAUGAGAGGCGAAA 12718 UUUCGCCUCUCAUCCCUAG DGAT2 73 12419 CAC CAGGAACUAUAU CUUU 12719 AAAGAUAUAGUU C CU GGU G DGAT2 74 12420 GUGGCAAUGCUAUCAUCAU 12720 AUGAUGAUAGCAUUGCCAC DGAT2 75 12421 GUGUUGAGGGAGUACCUGA 12721 U CAGGUACU C C CU CAACAC DGAT2 76 12422 CAGUUAGAU GAUU CACUUU 12722 AAAGU GAAU CAU CUAACU G DGAT2 77 12423 GUUCUGUUAUCUCUUGAUG 12723 CAU C AAGAGAU AAC AGAAC DGAT2 78 12424 U GU CAGACUUUU GUAUAU G 12724 CAUAUACAAAAGU CU GACA DGAT2 79 12425 UGGGUGUCUGUGGGUUAUU 12725 AAU AAC C CACAGACAC C C A DGAT2 80 12426 UCUGUGGGUUAUUUAAAAG 12726 CUUUUAAAUAAC C CACAGA DGAT2 81 12427 CAAAGAAUGGGAGUGGCAA 12727 UUGCCACUCCCAUUCUUUG DGAT2 82 12428 GCUGUGCUCUACUUCACUU 12728 AAGUGAAGUAGAGCACAGC DGAT2 83 12429 GAAU GAAGU GU AC AAG C AG 12729 CU GCUU GUACACUU CAUU C DGAT2 84 12430 CU CU GUAAAUUU GGAAGU G 12730 CACUU C CAAAUUUACAGAG DGAT2 85 12431 CAUGGAUGCAGCACAGACU 12731 AGUCUGUGCUGCAUCCAUG DGAT2 86 12432 C CUAGU CACU CAUAU C GGA 12732 U C C GAU AU GAGU GACU AG G DGAT2 87 12433 GCAGAUUAGUUCCAAAGCA 12733 UGCUUUGGAACUAAUCUGC DGAT2 88 12434 UGAGGGAGUACCUGAUGUC 12734 GACAU CAGGUACU C C CU CA DGAT2 89 12435 GUCAGACUUUUGUAUAUGC 12735 G CAUAUACAAAAGU CU GAC DGAT2 90 12436 GGUGCCUUCUGCAACUUCA 12736 UGAAGUUGCAGAAGGCACC DGAT2 91 12437 C GCU C GU CUAGU C CU GAAA 12737 UUUCAGGACUAGACGAGCG DGAT2 92 12438 UUGCCCUGUUCUAGGUGGU 12738 ACCACCUAGAACAGGGCAA DGAT2 93 12439 CUGUUCUAGGUGGUGGCUA 12739 U AG C CAC CAC CUAGAAC AG DGAT2 94 12440 U CAU GUACAUAUU CU GCAC 12740 GU G C AGAAU AU GU AC AU GA DGAT2 95 12441 CUGGCAAGAAUGCAGUCAC 12741 GUGACUGCAUUCUUGCCAG DGAT2 96 12442 U GAC C AC C AG GAACU AU AU 12742 AUAUAGUUCCUGGUGGUCA

[0741]

[0742] DGAT2_97 12443 CUGUGUUGAGGGAGUACCU 12743 AGGUACU C C CU CAACACAG DGAT2_98 12444 UUUCAAAGAAUGGGAGUGG 12744 C CACU C C CAUU CUUU GAAA DGAT2 99 12445 GUACAAGCAGGUGAUCUUC 12745 GAAGAU CAC CU GCUU GUAC DGAT2 100 12446 CUGAUGUCUGGAGGUAUCU 12746 AGAUAC CUC CAGACAU CAG DGAT2 101 12447 CUUUUGUAUAUGCCUUGAA 12747 UUCAAGGCAUAUACAAAAG DGAT2 102 12448 UAGGUGGAGUAACUGGUUU 12748 AAAC CAGUUACU C CAC CUA DGAT2 103 12449 GCUAGGUGGAGUAACUGGU 12749 AC CAGUUACU C CAC CUAGC DGAT2 104 12450 GGAGUGGCAAUGCUAUCAU 12750 AUGAUAGCAUUGCCACUCC DGAT2 105 12451 UUACCUGGCUACACUGGCA 12751 UGCCAGUGUAGCCAGGUAA DGAT2 106 12452 UUUCUUGGGUGGCUGAUGA 12752 U CAU C AG C C AC C C AAGAAA DGAT2 107 12453 CUAGGUGGUGGCUAAAUCU 12753 AGAUUUAGC CAC CAC CUAG DGAT2 108 12454 U C GU CUAGU CCU GAAACU G 12754 CAGUUU CAGGACUAGAC GA DGAT2 109 12455 U CU GUUAU CU CUU GAU GAG 12755 CU CAU CAAGAGAUAACAGA DGAT2 110 12456 CU CAU GUACAUAUU CU GCA 12756 U G C AGAAU AU GUAC AU GAG DGAT2 111 12457 UCUAGGUGGUGGCUAAAUC 12757 GAUUUAGC CAC CAC CUAGA DGAT2 112 12458 CAGUAGUAGGCAUCUGGAA 12758 UUCCAGAUGCCUACUACUG DGAT2 113 12459 GCUGGUGUUUGACUGGAAC 12759 GUU C C AGU C AAAC AC C AG C DGAT2 114 12460 UUACCUUCCCCAGAUCCUA 12760 UAGGAUCUGGGGAAGGUAA DGAT2 115 12461 UGGCUGAUGACAUGGAUGC 12761 GCAUCCAUGUCAUCAGCCA DGAT2 116 12462 GCCUCACUUUUCUGUGCCU 12762 AGGCACAGAAAAGUGAGGC DGAT2 117 12463 GUU C CAGAAAUACAUU GGU 12763 AC CAAU GUAUUU CU GGAAC DGAT2 118 12464 UUGGGUGGCUGAUGACAUG 12764 CAU GU CAU C AG C C AC C C AA DGAT2 119 12465 GCAGUAGUAGGCAUCUGGA 12765 UCCAGAUGCCUACUACUGC DGAT2 120 12466 GUACAUAUU CU GCACU GAU 12766 AU C AGU G C AGAAU AU GUAC DGAT2 121 12467 U C C C CAGAU C CUAGAUU CU 12767 AGAAUCUAGGAUCUGGGGA DGAT2 122 12468 GAAGUU C CAGAAAUACAUU 12768 AAU GUAUUU CU GGAACUU C DGAT2 123 12469 UUUCGAGACUACUUUCCCA 12769 UGGGAAAGUAGUCUCGAAA DGAT2 124 12470 UU C C C CAGAU C CUAGAUU C 12770 GAAUCUAGGAUCUGGGGAA DGAT2 125 12471 GGUGGCUGAUGACAUGGAU 12771 AU C CAU GU CAU C AG C C AC C DGAT2 126 12472 GUGUACAAGCAGGUGAUCU 12772 AGAU CAC CU GCUU GUACAC DGAT2 127 12473 GCACUGAUUGCUGGCUCAU 12773 AUGAGCCAGCAAUCAGUGC DGAT2 128 12474 UGCUGACCACCAGGAACUA 12774 UAGUUCCUGGUGGUCAGCA DGAT2 129 12475 GGGAGUGGCAAUGCUAUCA 12775 UGAUAGCAUUGCCACUCCC DGAT2 130 12476 GCAAUGCUAUCAUCAUCGU 12776 ACGAUGAUGAUAGCAUUGC DGAT2 131 12477 G C CAU CCU CAU GU AC AU AU 12777 AUAUGUACAUGAGGAUGGC DGAT2 132 12478 UUU GGAGAGAAU GAAGU GU 12778 ACACUU CAUU CU CU C CAAA DGAT2 133 12479 GAGUGGCAAUGCUAUCAUC 12779 GAUGAUAGCAUUGCCACUC DGAT2 134 12480 GAAC AC AC C C AAGAAAG GU 12780 ACCUUUCUUGGGUGUGUUC DGAT2 135 12481 CAUU GCAC CAU GU CAGACU 12781 AGUCUGACAUGGUGCAAUG DGAT2 136 12482 CUUGGCUGGUGUUUGACUG 12782 C AGU C AAAC AC C AG C C AAG DGAT2 137 12483 GU C CAGAAGAAGUU C CAGA 12783 UCUGGAACUUCUUCUGGAC DGAT2 138 12484 C C CUAGU CACU CAU AU C GG 12784 CCGAUAUGAGUGACUAGGG DGAT2 139 12485 U G GAAC AC AC C C AAGAAAG 12785 CUUUCUUGGGUGUGUUCCA DGAT2 140 12486 GUGCUCUACUUCACUUGGC 12786 GCCAAGUGAAGUAGAGCAC

[0743]

[0744] DGAT2 141 12487 CUACUUCACUUGGCUGGUG 12787 C AC C AG C C AAGU GAAGU AG DGAT2 142 12488 G GU GAAGAC AC AC AAC CU G 12788 CAGGUU GU GU GU CUU CAC C DGAT2 143 12489 UGUUGAGGGAGUACCUGAU 12789 AU CAGGUACU C C CU CAACA DGAT2 144 12490 GGCUCAGCUAACCUCUCUU 12790 AAGAGAGGUUAGCUGAGCC DGAT2 145 12491 UUGCCAUUAGUGACUUGGA 12791 UCCAAGUCACUAAUGGCAA DGAT2 146 12492 CAAC CCUCUCCUGUGUGUU 12792 AACACACAGGAGAGGGUUG DGAT2 147 12493 GAGCUAGGUGGAGUAACUG 12793 CAGUUACU C CAC CUAGCU C DGAT2 148 12494 UAUUCUGCACUGAUUGCUG 12794 CAGCAAUCAGUGCAGAAUA DGAT2 149 12480 GAAC AC AC C C AAGAAAG GU 12795 ACCUUUCUUGGGUGUGUUC DGAT2 150 12496 GUGGGUUAUUUAAAAGAAA 12796 UUU CUUUUAAAUAAC C CAC DGAT2 151 12497 CAGUUUAC CUU C C C CAGAU 12797 AUCUGGGGAAGGUAAACUG DGAT2 152 12498 CCAGUUUGAUCUCCCUUCU 12798 AGAAGGGAGAUCAAACUGG DGAT2 153 12499 GAGACUACUUU C C CAU C CA 12799 UGGAUGGGAAAGUAGUCUC DGAT2 154 12500 CAC C C CUAGU CACU CAU AU 12800 AUAUGAGUGACUAGGGGUG DGAT2 155 12501 CUU C C C CAGAU C CUAGAUU 12801 AAUCUAGGAUCUGGGGAAG DGAT2 156 12502 GGCUAAAUCUGGGCCUAAU 12802 AUUAGGCCCAGAUUUAGCC DGAT2 157 12503 CUAAAUCUGGGCCUAAUCU 12803 AGAUUAGGCCCAGAUUUAG DGAT2 158 12504 CUUUAUU GC CACUAC C C CA 12804 UGGGGUAGUGGCAAUAAAG DGAT2 159 12505 CU CAUACAAGC C C CUUUAU 12805 AUAAAGGGGCUUGUAUGAG DGAT2 160 12506 CUU CU CAUACAAGC C C CUU 12806 AAGGGGCUUGUAUGAGAAG DGAT2 161 12507 CGGCUUCCCGCGGGGCCGU 12807 ACGGCCCCGCGGGAAGCCG DGAT2 162 12508 GCUUCCCGCGGGGCCGUGA 12808 UCACGGCCCCGCGGGAAGC DGAT2 163 12509 GGCCGUGACUGGGCGGGCU 12809 AGCCCGCCCAGUCACGGCC DGAT2 164 12510 GCCGUGACUGGGCGGGCUU 12810 AAGCCCGCCCAGUCACGGC DGAT2 165 12511 CGUGACUGGGCGGGCUUCA 12811 UGAAGCCCGCCCAGUCACG DGAT2 166 12512 CUGGGCGGGCUUCAGCCAU 12812 AUGGCUGAAGCCCGCCCAG DGAT2 167 12513 GGGCGGGCUUCAGCCAUGA 12813 UCAUGGCUGAAGCCCGCCC DGAT2 168 12514 GGCGGGCUUCAGCCAUGAA 12814 UUCAUGGCUGAAGCCCGCC DGAT2 169 12515 CGGGACACCAUAGACUAUU 12815 AAU AGU CU AU G GU GU C C C G DGAT2 170 12516 GGGACACCAUAGACUAUUU 12816 AAAU AGU CU AU GGUGUCCC DGAT2 171 12517 GCUUUCAAAGAAUGGGAGU 12817 ACUCCCAUUCUUUGAAAGC DGAT2 172 12518 GGGUUAUUUAAAAGAAAUU 12818 AAUUU CUUUUAAAUAAC C C DGAT2 173 12519 CUUCUUCCCUUCCU GAAGU 12819 ACUUCAGGAAGGGAAGAAG DGAT2 174 12520 C C CUU C CU GAAGU GACAAA 12820 UUUGUCACUUCAGGAAGGG DGAT2 175 12521 CAGUCUUCUUGGGGAAGAA 12821 UU CUU C C C CAAGAAGACU G DGAT2 176 12522 CUUCUUGGGGAAGAAGGAU 12822 AU C CUU CUU C C C CAAGAAG DGAT2 177 12523 GAUUCACUUUUUGCCCCUA 12823 UAGGGGCAAAAAGUGAAUC DGAT2 178 12524 GUUUUUCUUGGGUGGCUGA 12824 U C AG C C AC C C AAGAAAAAC DGAT2 179 12525 GAAC C CAAGC CU CACUUUU 12825 AAAAGUGAGGCUUGGGUUC DGAT2 180 12526 CUCUUCUUCCCUUCCUGAA 12826 UUCAGGAAGGGAAGAAGAG DGAT2 181 12458 CAGUAGUAGGCAUCUGGAA 12827 UUCCAGAUGCCUACUACUG DGAT2 182 12460 UUACCUUCCCCAGAUCCUA 12828 UAGGAUCUGGGGAAGGUAA DGAT2 183 12463 GUU C CAGAAAUACAUU GGU 12829 AC CAAU GUAUUU CU GGAAC DGAT2 184 12466 GUACAUAUU CU GCACU GAU 12830 AU C AGU G C AGAAU AU GU AC

[0745]

[0746] DGAT2 185 12467 U C C C CAGAU C CUAGAUU CU 12831 AGAAUCUAGGAUCUGGGGA DGAT2 186 12468 GAAGUU C CAGAAAUACAUU 12832 AAU GUAUUU CU GGAACUU C DGAT2 187 12469 UUUCGAGACUACUUUCCCA 12833 UGGGAAAGUAGUCUCGAAA DGAT2 188 12472 GUGUACAAGCAGGUGAUCU 12834 AGAU CAC CU GCUU GUACAC DGAT2 189 12475 GGGAGUGGCAAUGCUAUCA 12835 UGAUAGCAUUGCCACUCCC DGAT2 190 12476 GCAAUGCUAUCAUCAUCGU 12836 ACGAUGAUGAUAGCAUUGC DGAT2 191 12477 G C GAU CCU C AU GU AC AU AU 12837 AUAUGUACAUGAGGAUGGC DGAT2 192 12481 CAUU GCAC CAU GU CAGACU 12838 AGUCUGACAUGGUGCAAUG DGAT2 193 12483 GU C CAGAAGAAGUU C CAGA 12839 UCUGGAACUUCUUCUGGAC DGAT2 194 12489 UGUUGAGGGAGUACCUGAU 12840 AU CAGGUACU C C CU CAACA DGAT2 195 12492 CAAC CCUCUCCUGUGUGUU 12841 AACACACAGGAGAGGGUUG DGAT2 196 12542 CUUCACUUGGCUGGUGUUU 12842 AAAC AC C AG C C AAGU GAAG DGAT2 197 12543 CU C GU CUAGU CCU GAAACU 12843 AGUUU CAGGACUAGAC GAG DGAT2 198 12544 GAGCAGCAGAUUAGUUCCA 12844 UGGAACUAAUCUGCUGCUC DGAT2 199 12545 GAGGGAGUACCUGAUGUCU 12845 AGACAU CAGGUACU C C CU C DGAT2 200 12546 CUGACCUGGUUCCCAUCUA 12846 UAGAUGGGAACCAGGUCAG DGAT2 201 12547 GACU G GAAC AC AC C C AAGA 12847 UCUUGGGUGUGUUCCAGUC DGAT2 202 12548 UUGAGGGAGUACCUGAUGU 12848 ACAU CAGGUACU C C CU CAA DGAT2 203 12549 GCAAGAAUGCAGUCACCCU 12849 AGGGUGACUGCAUUCUUGC DGAT2 204 12550 GAAUGGGAGUGGCAAUGCU 12850 AGCAUUGCCACUCCCAUUC DGAT2 205 12551 GAAUGCCUGUGUUGAGGGA 12851 UCCCUCAACACAGGCAUUC DGAT2 206 12552 UUCGAGACUACUUUCCCAU 12852 AUGGGAAAGUAGUCUCGAA DGAT2 207 12553 CUUU C GAGACUACUUU C C C 12853 GGGAAAGUAGUCUCGAAAG DGAT2 208 12554 CAAGGGCUUUGUGAAACUG 12854 CAGUUU CACAAAGC C CUU G DGAT2 209 12555 CAAUUUU GCUAAAC CAUUA 12855 UAAUGGUUUAGCAAAAUUG DGAT2 210 12556 CAGACUUUUGUAUAUGCCU 12856 AGGCAUAUACAAAAGUCUG DGAT2 211 12557 GAAAGC CACUU CU CAUACA 12857 UGUAUGAGAAGUGGCUUUC DGAT2 212 12558 CAGGAACUAUAUCUUUGGA 12858 U C CAAAGAUAUAGUU C CU G DGAT2 213 12559 CAUGAGCUAGGUGGAGUAA 12859 UUACU C CAC CUAGCU CAU G DGAT2 214 12560 CAU GUACAUAUU CU GCACU 12860 AGU G C AGAAU AU GU AC AU G DGAT2 215 12561 C GCUACUUU C GAGACUACU 12861 AGUAGUCUC GAAAGU AG C G DGAT2 216 12562 CUUCUGCAACUUCAGCACA 12862 UGUGCUGAAGUUGCAGAAG DGAT2 217 12563 CAC CAU GU CAGACUUUU GU 12863 AC AAAAGU CU GAC AU G GU G DGAT2 218 12564 CUU GAAAAUAAAU GAAAGU 12864 ACUUUCAUUUAUUUUCAAG DGAT2 219 12565 GCCGAUGGGUCCAGAAGAA 12865 UUCUUCUGGACCCAUCGGC DGAT2 220 12566 GGUCACAGUGGGUCCGAAA 12866 UUUCGGACCCACUGUGACC DGAT2 221 12567 UGUGGGUUAUUUAAAAGAA 12867 UU CUUUUAAAUAAC C CACA DGAT2 222 12568 UU GACU GGAACACAC C CAA 12868 UUGGGUGUGUUCCAGUCAA DGAT2 223 12569 C GAAC C CAAGC CU CACUUU 12869 AAAGUGAGGCUUGGGUUCG DGAT2 224 12570 AAAGAAUGGGAGUGGCAAU 12870 AUUGCCACUCCCAUUCUUU DGAT2 225 12571 UUUACCUUCCCCAGAUCCU 12871 AGGAUCUGGGGAAGGUAAA DGAT2 226 12572 CAGUUUGAUCUCCCUUCUG 12872 CAGAAGGGAGAUCAAACUG DGAT2 227 12573 U CAC C C CUAGU CACU CAUA 12873 UAUGAGUGACUAGGGGUGA DGAT2 228 12574 U CAGUUUAC CUU C C C CAGA 12874 UCUGGGGAAGGUAAACUGA

[0747]

[0748] DGAT2_229 12575 CCUAGGGAUGAGAGGCGAA 12875 UUCGCCUCUCAUCCCUAGG DGAT2 230 12576 ACUCAGUCUUCUUGGGGAA 12876 UU C C C CAAGAAGACU GAGU DGAT2 231 12577 UUUGAUCUCCCUUCUGCCA 12877 UGGCAGAAGGGAGAUCAAA DGAT2 232 12578 UGGCUAAAUCUGGGCCUAA 12878 UUAGGCCCAGAUUUAGCCA DGAT2 233 12579 GUGGCUAAAUCUGGGCCUA 12879 UAGGCCCAGAUUUAGCCAC DGAT2 234 12580 GAGCUGACCUGGUUCCCAU 12880 AUGGGAACCAGGUCAGCUC DGAT2 235 12581 GAAACUCAGUCUUCUUGGG 12881 C C CAAGAAGACU GAGUUU C DGAT2 236 12582 GGAGGUAUCUGCCCUGUCA 12882 UGACAGGGCAGAUACCUCC DGAT2 237 12583 UUU GACU GGAACACAC C GA 12883 UGGGUGUGUUCCAGUCAAA DGAT2 238 12584 GCCUAAUCUGGGUGGCUCA 12884 UGAGCCACCCAGAUUAGGC DGAT2 239 12585 GCCGGGACACCAUAGACUA 12885 UAGUCUAUGGUGUCCCGGC DGAT2 240 12586 AAUGGGAGUGGCAAUGCUA 12886 UAGCAUUGCCACUCCCAUU DGAT2 241 12587 GCAGGAGGUCACAGUGGGU 12887 ACCCACUGUGACCUCCUGC DGAT2 242 12588 GGCCGAUGGGUCCAGAAGA 12888 UCUUCUGGACCCAUCGGCC DGAT2 243 12589 GGAGCACCCAACCCAGCAA 12889 UUGCUGGGUUGGGUGCUCC DGAT2 244 12590 GGCUGGUGCCCUACUCCAA 12890 UUGGAGUAGGGCACCAGCC DGAT2 245 12591 ACU G GAAC AC AC C C AAGAA 12891 UUCUUGGGUGUGUUCCAGU DGAT2 246 12592 CUGCUGGGGUCUAGGCUGU 12892 ACAGCCUAGACCCCAGCAG DGAT2 247 12593 CUGGGUGCCUUCUGCAACU 12893 AGUUGCAGAAGGCACCCAG DGAT2 248 12594 AUACAUUGGUUUCGCCCCA 12894 UGGGGCGAAACCAAUGUAU DGAT2 249 12595 GCUAAAUCUGGGCCUAAUC 12895 GAUUAGGCCCAGAUUUAGC DGAT2 250 12596 GGGCCUAAUCUGGGUGGCU 12896 AGCCACCCAGAUUAGGCCC DGAT2 251 12597 GAAACUGGCCCUGCGUCAU 12897 AUGACGCAGGGCCAGUUUC DGAT2 252 12598 GCCUGGGUGCCUUCUGCAA 12898 UUGCAGAAGGCACCCAGGC DGAT2 253 12599 U CU CAUACAAGC C C CUUUA 12899 UAAAGGGGCUUGUAUGAGA DGAT2 254 12600 CAAGC C CAU CAC CACU GUU 12900 AACAGUGGUGAUGGGCUUG DGAT2 255 12601 GUCCGAAACUGGGCUGUGU 12901 ACACAGCCCAGUUUCGGAC DGAT2 256 12602 CCCUAGGGAUGAGAGGCGA 12902 UCGCCUCUCAUCCCUAGGG DGAT2 257 12603 AUGGGUGUCUGUGGGUUAU 12903 AU AAC C C AC AGAC AC C CAU DGAT2 258 12604 GCUUUGUGAAACUGGCCCU 12904 AGGGCCAGUUUCACAAAGC DGAT2 259 12605 GGGUGGCUGAUGACAUGGA 12905 UCCAUGUCAUCAGCCACCC DGAT2 260 12606 C CAAC C CU CU C CU GU GU GU 12906 ACACACAGGAGAGGGUUGG DGAT2 261 12607 CAGUUGCCCCGUUGUGUGA 12907 UCACACAACGGGGCAACUG DGAT2 262 12608 GGUGGCUAAAUCUGGGCCU 12908 AGGCCCAGAUUUAGCCACC DGAT2 263 12609 AUGGGAGUGGCAAUGCUAU 12909 AUAGCAUUGCCACUCCCAU DGAT2 264 12610 CCU CAC C C CUAGU CACU CA 12910 UGAGUGACUAGGGGUGAGG DGAT2 265 12611 CCCAAGCUGGAGCACCCAA 12911 UUGGGUGCUCCAGCUUGGG DGAT2 266 12612 GUCUGGAGGUAUCUGCCCU 12912 AGGGCAGAUACCUCCAGAC DGAT2 267 12613 AAGUGUCAUGGGUGUCUGU 12913 ACAGACAC C CAU GACACUU DGAT2 268 12614 C C CUACU C CAAGC C CAU CA 12914 UGAUGGGCUUGGAGUAGGG DGAT2 269 12615 GGUUUCGCCCCAUGCAUCU 12915 AGAUGCAUGGGGCGAAACC DGAT2 270 12616 GGGCUGUGUGGCGCUACUU 12916 AAGUAGCGCCACACAGCCC DGAT2 271 12617 CU CAC C C CUAGU CACU CAU 12917 AUGAGUGACUAGGGGUGAG DGAT2 272 12618 C CUU C C C CAGAU C CUAGAU 12918 AUCUAGGAUCUGGGGAAGG

[0749]

[0750] DGAT2_273 12619 GGAGCUGACCUGGUUCCCA 12919 UGGGAACCAGGUCAGCUCC DGAT2 274 12620 GGGUCCGAAACUGGGCUGU 12920 ACAGCCCAGUUUCGGACCC DGAT2 275 12621 GCUGGGGUCUAGGCUGUUU 12921 AAACAGCCUAGACCCCAGC DGAT2 276 12622 GUCAUGGGUGUCUGUGGGU 12922 AC C C AC AGAC AC C C AU GAC DGAT2 277 12623 C C GAAC C CAAGC CU CACUU 12923 AAGUGAGGCUUGGGUUCGG DGAT2 278 12624 ACUACUUU C C GAU C CAGCU 12924 AGCUGGAUGGGAAAGUAGU DGAT2 279 12625 C C AAG C C GAU C AC C ACU GU 12925 ACAGUGGUGAUGGGCUUGG DGAT2 280 12626 GGGGAGGAAACCCAACCCU 12926 AGGGUUGGGUUUCCUCCCC DGAT2 281 12627 AACUCAGUCUUCUUGGGGA 12927 U C C C CAAGAAGACU GAGUU DGAT2 282 12628 CCU CAGUUUAC CUU C C C CA 12928 UGGGGAAGGUAAACUGAGG DGAT2 283 12629 CCCAUCCAGCUGGUGAAGA 12929 UCUUCACCAGCUGGAUGGG DGAT2 284 12630 GAGGUCACAGUGGGUCCGA 12930 UCGGACCCACUGUGACCUC DGAT2 285 12631 CUGGAGGUAUCUGCCCUGU 12931 ACAGGGCAGAUACCUCCAG DGAT2 286 12632 C CUAC CU CAC C C CUAGU CA 12932 UGACUAGGGGUGAGGUAGG DGAT2 287 12633 AC C CAAGC CU CACUUUU CU 12933 AGAAAAGUGAGGCUUGGGU DGAT2 288 12634 GGAACCGCAAGGGCUUUGU 12934 ACAAAGCCCUUGCGGUUCC DGAT2 289 12635 C C C GAAC C CAAGC CU CACU 12935 AGUGAGGCUUGGGUUCGGG DGAT2 290 12636 GCUGACCUGGUUCCCAUCU 12936 AGAUGGGAACCAGGUCAGC DGAT2 291 12637 GUUAGAUGAUUCACUUUUU 12937 AAAAAGU GAAU GAU CUAAC DGAT2 292 12638 GGAACUAUAUCUUUGGAUA 12938 UAU C CAAAGAUAUAGUU C C DGAT2 293 12639 GACUAUUU GCUUU CAAAGA 12939 U CUUU GAAAGCAAAUAGU C DGAT2 294 12640 CUAUUU GCUUU CAAAGAAU 12940 AUU CUUU GAAAGCAAAUAG DGAT2 295 12641 GCUAAAC CAUUACAAU GUU 12941 AACAUUGUAAUGGUUUAGC DGAT2 296 12642 CUAAAC CAUUACAAU GUUA 12942 UAACAUU GUAAU GGUUUAG DGAT2 297 12643 GGAAAAAGU CAGUAUUU CA 12943 U GAAAUACU GACUUUUU C C DGAT2 298 12644 GAAAAAGU CAGUAUUU CAA 12944 UUGAAAUACUGACUUUUUC DGAT2 299 12645 GGAGUAACUGGUUUUUCUU 12945 AAGAAAAAC CAGUUACU C C DGAT2 300 12646 AUAGACUAUUUGCUUUCAA 12946 UU GAAAGCAAAUAGU CUAU

[0751]

[0752] Table 17: selected modified DGAT2 sense and antisense modified nucleotide sequences. fA, fll, fC, fG = 2’-F ribonucleotides and mA, mil, mC, mG = 2’ OMe ribonucleotides.

[0753] SEQ SEQ Modified sense DGAT2 Modified antisense DGAT2 ID ID sequences sequences

[0754] NOs: NOs:

[0755] 17256 17541 DGAT- mUmGmGmGmUmUfAfUfUmU mUfUmUfCmUfUmUfUmAfAmAfU 1473 mAmAmAmAmGmAmAmA mAfAmCfCmCfAmCmA 17257 17542 DGAT2_1 mCmUmGmU mAm AfAfUf U mU mGfAmCfAmCfUmUfCmCfAmAfA mGmGmAmAmGmUmGmUmC mUfUmUfAmCfAmGmUmU 17258 17543 DGAT2_2 mCmCmAmUmGmAfGfCfUmA mUfAmCfUmCfCmAfCmCfUmAfG mGmGmUmGmGmAmGmUmA mCfUmCfAmUfGmGmUmU 17259 17544 DGAT2_3 mCmCmAmCmCmAfGfGfAmA mAfAmGfAmUfAmUfAmGfUmUfC mCmUmAmUmAmUmCmUmU mCfUmGfGmUfGmGmUmU 17260 17545 DGAT2_4 mUmCmCmAmGmAfAfAfUmA mAfAmAfCmCfAmAfUmGfUmAfU mCmAmUmUmGmGmUmUmU mUfUmCfUmGfGmAmUmU 17261 17546 DGAT2_5 mCmCmGmCmAmAfGfGfGmC mUfUmUfCmAfCmAfAmAfGmCfC mUmUmUmGmUmGmAmAmA mCfUmUfGmCfGmGmUmU 17262 17547 DGAT2_6 mGmCmAmAmGmAfAfGfUmU mAfUmGfCmCfUmGfGmGfAmAfC

[0756]

[0757] mCmCmCmAmGmGmCmAmU mUfUmCfUmUfGmCmUmU 17263 17548 DGAT2_7 mCmAmUmGmGmGfUfGfUmC mUfAmAfC mCfC mAfC m AfG m AfC mUmGmUmGmGmGmUmUmA mAfC mCfC mAfU mG m U mU 17264 17549 DGAT2_8 mUmCmUmGmUmAfAfAfUmU mAfCmAfCmUfUmCfCmAfAmAfU mUmGmGmAmAmGmUmGmU mUfUmAfCmAfGmAmUmU 17265 17550 mUmUmGmGmAmGfAfGfAmA mUfAmCfAmCfUmUfCmAfUmUfC DGAT2 9 mUmGmAmAmGmUmGmUmA mUfCmUfCmCfAmAmUmU 17266 17551 DGAT2_10 mCmCmAmGmUmUfAfGfAmU mAfAmGfUmGfAmAfUmCfAmUfC mGmAmUmUmCmAmCmUmU mUfAmAfCmUfGmGmUmU 17267 17552 DGAT2_11 mCmGmAmUmGmGfGfUfCmC mAfCmUfUmCfUmUfCmUfGmGfA mAmGmAmAmGmAmAmGmU mCfC mCf AmUfC mG m U mU 17268 17553 DGAT2_12 mG mC m AmG mC mAfGfAfU mU mUfUmUfGmGfAmAfCmUfAmAfU mAmGmUmUmCmCmAmAmA mCfUmGfCmUfGmCmUmU 17269 17554 DGAT2_13 mG mUmC mUmG mUfGfGfG mU mUfUmUfUmAfAmAfUmAfAmCfC mUmAmUmUmUmAmAmAmA mCfAmCfAmGfAmCmUmU 17270 17555 DGAT2_14 mUmCmAmCmUmUfGfGfCmU mUfCmAfAmAfCmAfCmCfAmGfC mGmGmUmGmUmUmUmGmA mCfAmAfGmUfGmAmUmU 17271 17556 DGAT2_15 mCmCmUmUmUmGfGfAfGmA mAfCmUfUmCfAmUfUmCfUmCfU mG mAmAm U mG m AmAmG mU mCfC mAf AmAfG mG m U mU 17272 17557 DGAT2_16 mCmCmAmUmCmCfUfCfAmU mAfAmUfAmUfGmUfAmCfAmUfG mGmUmAmCmAmUmAmUmU mAfG mGf AmUfG mG m U mU 17273 17558 DGAT2_17 mGmCmAmAmGmGfGfCfUmU mAfGmUfUmUfCmAfCmAfAmAfG mUmGmUmGmAmAmAmCmU mCfCmCfUmUfGmCmUmU 17274 17559 DGAT2_18 mGmCmGmAmAmAfGfCfCmA mUfAmUfG mAfG mAfAmGfUmGfG mCmUmUmCmUmCmAmUmA mCfUmUfUmCfGmCmUmU 17275 17560 DGAT2_19 mC m AmAmG mAmAfGfUf U mC mUfAmUfGmCfCmUfGmGfGmAfA mCmCmAmGmGmCmAmUmA mCfUmUfCmUfUmGmUmU 17276 17561 DGAT2_20 mUmGmUmAmCmAfAfGfCmA mAfAmGfAmUfCmAfCmCfUmGfC mGmGmUmGmAmUmCmUmU mUfUmGfUmAfCmAmUmU 17277 17562 DGAT2_21 mUmGmUmUmCmUfAfGfGmU mUfUmAfGmCfCmAfCmCfAmCfC mGmGmUmGmGmCmUmAmA mUfAmGfAmAfCmAmUmU 17278 17563 DGAT2_22 mUmGmGmAmCmCfAfGfUmU mGfAmAfUmCfAmUfCmUfAmAfC mAmGmAmUmGmAmUmUmC mUfGmGfUmCfCmAmUmU 17279 17564 DGAT2_23 mCmUmGmAmCmCfAfCfCmA mUfAmUfAmGfUmUfCmCfUmGfG mG mG m AmAmC m U mAmU mA mUfGmGfUmCfAmGmUmU 17280 17565 DGAT2_24 mGmCmUmCmUmGfUfAfAmA mAfCmUfUmCfCmAfAmAfUmUfU mUmUmUmGmGmAmAmGmU mAfC mAfG mAfG mC m U m U 17281 17566 DGAT2_25 mGmAmUmGmGmGfUfCfCmA mAfAmCfUmUfCmUfUmCfUmGfG mG mAmAmG mAm AmG m U mU mAfC mCfC mAfU mC m U mU 17282 17567 DGAT2_26 mUmGmGmAmGmAfGfAfAmU mGfUmAfCmAfCmUfUmCfAmUfU mGmAmAmGmUmGmUmAmC mCfUmCfUmCfCmAmUmU 17283 17568 DGAT2_27 mGmCmAmCmCmAfUfGfUmC mCfAmAfAmAfGmUfCmUfGmAfC mAmGmAmCmUmUmUmUmG mAfUmGfGmUfGmCmUmU 17284 17569 DGAT2_28 mGmCmGmCmUmAfCfUfUmU mGfUmAfGmUfCmUfCmGfAmAfA mCmGmAmGmAmCmUmAmC mGfUmAfGmCfGmCmUmU 17285 17570 DGAT2_29 mC mCmAmUmU mAfGfUfG mA mUfGmGfUmCfCmAfAmGfUmCfA mCmUmUmGmGmAmCmCmA mCfU mAf AmUfG mG m U mU 17286 17571 DGAT2_30 mGmUmCmUmAmGfUfCfCmU mUfGmCfAmGfUmUfUmCfAmGfG mG mAmAm AmC mU mG mC mA mAfC mUfAmGf AmC m U mU 17287 17572 DGAT2_31 mCmUmGmUmGmGfGfUfU mA mUfCmUfUmUfUmAfAmAfUmAfA mUmUmUmAmAmAmAmGmA mCfC mCf AmCf AmG m U mU 17288 17573 DGAT2_32 mCmUmUmGmGmGfUfGfGmC mAfUmGfUmCfAmUfCmAfGmCfC mUmGmAmUmGmAmCmAmU mAfC mCfC mAfAmG m U mU 17289 17574 DGAT2_33 mUmGmCmCmUmGfUfGfUmU mUfAmCfUmCfCmCfUmCfAmAfC mGmAmGmGmGmAmGmUmA mAfC mAfG mGfC mAm U mU 17290 17575 DGAT2_34 mUmGmUmCmUmGfUfGfGmG mUfUmUfAmAfAmUfAmAfCmCfC mUmUmAmUmUmUmAmAmA mAfC mAfG mAfC mAm U m U 17291 17576 DGAT2_35 mUmUmCmCmAmGfAfAfAmU mAfAmCfCmAfAmUfGmUfAmUfU mAmCmAmUmUmGmGmUmU mUfCmUfGmGfAmAmUmU 17292 17577 DGAT2_36 mUmGmAmGmCmUfAfGfGmU mAfGmUfUmAfCmUfCmCfAmCfC mGmGmAmGmUmAmAmCmU mUfAmGfCmUfCmAmUmU 17293 17578 DGAT2_37 mUmAmCmAmUmAfUfUfCmU mAfAmUfCmAfGmUfGmCfAmGfA mGmCmAmCmUmGmAmUmU mAfUmAfUmGfUmAmUmU 17294 17579 DGAT2_38 mG mAmAmG m U mGfAfGfC mA mGfGmAfAmCfUmUfCmUfUmGfC mAmGmAmAmGmUmUmCmC mUfCmAfCmUfUmCmUmU

[0758]

[0759] 17295 17580 DGAT2_39 mGmGmUmGmUmCfUfGfUmG mUfAmAfAmUfAmAfCmCfCmAfC mGmGmUmUmAmUmUmUmA m Af G m Af C m AfC mC m U m U 17296 17581 DGAT2_40 mU mC mAm U mG mGf AfGfC mU mAfAmCfCmAfGmGfUmCfAmGfC mGmAmCmCmUmGmGmUmU mUfCmCfAmUfGmAmUmU 17297 17582 DGAT2_41 mC mU mG mAmG mCf AfGfC mA mGfAmAfCmUfAmAfUmCfUmGfC mGmAmUmUmAmGmUmUmC mUfGmCfUmCfAmGmUmU 17298 17583 DGAT2_42 mGmGmUmCmUmAfGfGfCmU mGfAmGfAmGfAmAfAmCfAmGfC mGmUmUmUmCmUmCmUmC mCfUmAfGmAfCmCmUmU 17299 17584 DGAT2_43 mC mAmG mAm U mUfAfGfU mU mCfUmGfCmUfUmUfGmGfAmAfC mCmCmAmAmAmGmCmAmG mUfAmAfUmCfUmGmUmU 17300 17585 DGAT2_44 mCmGmCmAmAmGfGfGfCmU mGfUmUfUmCfAmCfAmAfAmGfC mUmUmGmUmGmAmAmAmC mCfCmUfUmGfCmGmUmU 17301 17586 DGAT2_45 mC mC mAmG mG mAf AfCfU mA mCfCmAfAmAfGmAfUmAfUmAfG mUmAmUmCmUmUmUmGmG mUfUmCfCmUfGmGmUmU 17302 17587 DGAT2_46 mG mAmAmG m U mGf UfAfC mA mUfCmAfCmCfUmGfCmUfUmGfU mAmGmCmAmGmGmUmGmA mAfCmAfCmUfUmCmUmU 17303 17588 DGAT2_47 mUmCmCmUmCmAfUfGfUmA mCfAmGfAmAfUmAfUmGfUmAfC mCmAmUmAmUmUmCmUmG mAf U mGf AmGfG mAm U mU 17304 17589 DGAT2_48 mCmGmUmCmU mAfGfUfC mC mGfCmAfGmUfUmUfCmAfGmGfA mUmGmAmAmAmCmUmGmC mCf U mAfG mAfC mG m U mU 17305 17590 DGAT2_49 mG mG m AmC mC mAfGfUfU mU mUfUmGfGmCfAmGfAmGfAmAfA mCmUmCmUmGmCmCmAmA mCfUmGfGmUfCmCmUmU 17306 17591 DGAT2_50 mGmGmGmUmGmUfCfUfGmU mAfAmAfUmAfAmCfCmCfAmCfA mGmGmGmUmUmAmUmUmU mGfAmCf AmCfC mC m U mU 17307 17592 DGAT2_51 mG mG mAmAmC m AfCfAfC mC mCfCmUfUmUfCmUfUmGfGmGf mC mAmAmG m AmAmAmG mG UmGfUmGfUmUfCmCmUmU 17308 17593 DGAT2_52 mC mCmAmUmG mUfCfAfG mA mAfUmAfCmAfAmAfAmGfUmCfU mCmUmUmUmUmGmUmAmU mGfAmCfAmUfGmGmUmU 17309 17594 DGAT2_53 mC m AmAmAmG mGfAfAf AmC mGfAmAfGmAfCmUfGmAfGmUfU mUmCmAmGmUmCmUmUmC mUfCmCfUmUfUmGmUmU 17310 17595 DGAT2_54 mUmUmCmUmGmUfUfAfUmC mUfCmAfUmCfAmAfGmAfGmAfU mUmCmUmUmGmAmUmGmA mAf AmCf AmGf AmAm U mU 17311 17596 DGAT2_55 mGmUmGmUmCmUfGfUfGmG mUfUmAfAmAfUmAfAmCfCmCfA mGmUmUmAmUmUmUmAmA mCfAmGf AmCf AmC m U mU 17312 17597 DGAT2_56 mC mAmU mG m U mCf AfGf AmC mUfAmUfAmCfAmAfAmAfGmUfC mUmUmUmUmGmUmAmUmA mUfGmAfCmAfUmGmUmU 17313 17598 DGAT2_57 mUmCmGmCmUmGfUfGfCmU mGfUmGfAmAfGmUfAmGfAmGfC mCmUmAmCmUmUmCmAmC mAfC mAfG mCfG mAm U mU 17314 17599 DGAT2_58 mUmGmGmCmAmAfUfGfCmU mGfAmUfGmAfUmGfAmUfAmGfC mAm U mC mAm U mC mAm U mC mAfUmUfGmCfCmAmUmU 17315 17600 DGAT2_59 mU mC mAmAm AmGfAfAf U mG mUfGmCfCmAfCmUfCmCfCmAfU mGmGmAmGmUmGmGmCmA mUfCmUfUmUfGmAmUmU 17316 17601 DGAT2_60 mGmGmGmUmCmCfAfGfAmA mUfGmGfAmAfCmUfUmCfUmUfC mGmAmAmGmUmUmCmCmA mUfGmGfAmCfCmCmUmU 17317 17602 DGAT2_61 mUmCmAmUmGmGfGfUfGmU mAfAmCfCmCfAmCfAmGfAmCfA mCmUmGmUmGmGmGmUmU mCfCmCfAmUfGmAmUmU 17318 17603 DGAT2_62 mC mU mG mG m AmAfCfAfC mA mUfUmUfCmUfUmGfGmGfUmGf mCmCmCmAmAmGmAmAmA UmGfUmUfCmCfAmGmUmU 17319 17604 DGAT2_63 mGmCmUmAmCmUfUfUfCmG mAfAmGfUmAfGmUfCmUfCmGfA mAmGmAmCmUmAmCmUmU mAf AmGf U mAfG mC m U mU 17320 17605 DGAT2_64 mGmCmAmGmUmGfCfCfAmU mUfAmCfAmUfGmAfGmGfAmUfG mCmCmUmCmAmUmGmUmA mGfCmAfCmUfGmCmUmU 17321 17606 DGAT2_65 mUmUmGmCmUmCfUfGfUmA mUfUmCfCmAfAmAfUmUfUmAfC mAmAmUmUmUmGmGmAmA mAfG mAfG mCf AmAm U mU 17322 17607 DGAT2_66 mG mG mAmG mAmGfAfAf U mG mUfGmUfAmCfAmCfUmUfCmAfU mAmAmG m U mG m U mAmC mA mUfCmUfCmUfCmCmUmU 17323 17608 DGAT2_67 mU m U mC mC mC m AfUfCfC mA mUfUmCfAmCfCmAfGmCfUmGfG mGmCmUmGmGmUmGmAmA mAf U mGfG mGfAmAm U mU 17324 17609 DGAT2_68 mGmUmUmCmUmAfGfGfUmG mUfUmUfAmGfCmCfAmCfCmAfC mGmUmGmGmCmUmAmAmA mCfU mAfG mAf AmC m U mU 17325 17610 DGAT2_69 mC m U mAmG mG m UfGfGf AmG mAfAmCfCmAfGmUfUmAfCmUfC mUmAmAmCmUmGmGmUmU mCfAmCfCmUfAmGmUmU 17326 17611 DGAT2_70 mCmUmAmCmUmUfUfCfGmA mAfAmAfGmUfAmGfUmCfUmCfG mGmAmCmUmAmCmUmUmU mAfAmAfGmUfAmGmUmU 17327 17612 DGAT2_71 mG mG mC mG mAmAf AfGfC mC mAfUmGfAmGfAmAfGmUfGmGfC

[0760]

[0761] mAmCmUmUmCmUmCmAmU mUfUmUfCmGfCmCmUmU 17328 17613 DGAT2_72 mC mU mAmG mG mGf AfUfG mA mUfUmUfCmGfCmCfUmCfUmCfA mGmAmGmGmCmGmAmAmA mUfCmCfCmUfAmGmUmU 17329 17614 DGAT2_73 mCmAmCmCmAmGfGfAfAmC mAfAmAfGmAfUmAfUmAfGmUfU mUmAmUmAmUmCmUmUmU mCfCmUfGmGfUmGmUmU 17330 17615 DGAT2_74 mGmUmGmGmCmAfAfUfGmC mAfUmGfAmUfGmAfUmAfGmCfA mUmAmUmCmAmUmCmAmU mUfUmGfCmCfAmCmUmU 17331 17616 DGAT2_75 mGmUmGmUmUmGfAfGfGmG mUfCmAfGmGfUmAfCmUfCmCfC mAmGmUmAmCmCmUmGmA mUfCmAfAmCfAmCmUmU 17332 17617 DGAT2_76 mCmAmGmUmUmAfGfAfUmG mAfAmAfG mUfG m AfAm UfC m AfU mAmUmUmCmAmCmUmUmU mCfU mAf AmCfU mG m U mU 17333 17618 DGAT2_77 mGmUmUmCmUmGfUfUfAmU mCfAmUfCmAfAmGfAmGfAmUfA mCmUmCmUmUmGmAmUmG mAfC mAfG mAf AmC m U mU 17334 17619 DGAT2_78 mU mG m U mC m AmGf AfCf U mU mCfAmUfAmUfAmCfAmAfAmAfG mUmUmGmUmAmUmAmUmG mUfCmUfGmAfCmAmUmU 17335 17620 DGAT2_79 mUmGmGmGmUmGfUfCfUmG mAf AmUf AmAfC mCfC m AfC mAfG mUmGmGmGmUmUmAmUmU mAfCmAfCmCfCmAmUmU 17336 17621 DGAT2_80 mUmCmUmGmUmGfGfGfUmU mCfUmUfUmUfAmAfAmUfAmAfC mAmUmUmUmAmAmAmAmG mC fC m Af C m AfG m Am U m U 17337 17622 DGAT2_81 mCmAmAmAmGmAfAfUfGmG mUfUmGfCmCfAmCfUmCfCmCfA mGmAmGmUmGmGmCmAmA mUfUmCfUmUfUmGmUmU 17338 17623 DGAT2_82 mGmCmUmGmUmGfCfUfCmU mAfAmGfUmGfAmAfGmUfAmGfA mAmCmUmUmCmAmCmUmU mG fC mAf C mAfG mC m U m U 17339 17624 DGAT2_83 mG mAmAm U mG m AfAfGf U mG mCfUmGfCmUfUmGfUmAfCmAfC mUmAmCmAmAmGmCmAmG mUfUmCfAmUfUmCmUmU 17340 17625 DGAT2_84 mC m U mC m U mG m UfAfAf AmU mCfAmCfUmUfCmCfAmAfAmUfU mUmUmGmGmAmAmGmUmG mUfAmCfAmGfAmGmUmU 17341 17626 DGAT2_85 mCmAmUmGmGmAfUfGfCmA mAfGmUfCmUfGmUfGmCfUmGf mGmCmAmCmAmGmAmCmU C mAfU mCfC mAfU mG m U mU 17342 17627 DGAT2_86 mCmCmUmAmGmUfCfAfCmU mUfCmCfGmAfUmAfUmGfAmGfU mCmAmUmAmUmCmGmGmA mGfAmCf U mAfG mG m U mU 17343 17628 DGAT2_87 mGmCmAmGmAmUfUfAfGmU mUfGmCfUmUfUmGfGmAfAmCfU mUmCmCmAmAmAmGmCmA mAfAmUfCmUfGmCmUmU 17344 17629 DGAT2_88 mUmGmAmGmGmGfAfGfUmA mGfAmCfAmUfCmAfGmGfUmAfC mCmCmUmGmAmUmGmUmC mUfCmCfCmUfCmAmUmU 17345 17630 DGAT2_89 mGmUmCmAmGmAfCfUfUmU mGfC mAfU mAfU mAfC mAfAm AfA mUmGmUmAmUmAmUmGmC mGfUmCfUmGfAmCmUmU 17346 17631 DGAT2_90 mGmGmUmGmCmCfUfUfCmU mUfGmAfAmGfUmUfGmCfAmGfA mGmCmAmAmCmUmUmCmA m Af G mG fC m Af C mC m U m U 17347 17632 DGAT2_91 mCmGmCmUmCmGfUfCfUmA mUfUmUfC mAfG mGfAmCfU mAfG mGmUmCmCmUmGmAmAmA mAfC mGfAmGfCmGmUmU 17348 17633 DGAT2_92 mUmUmGmCmCmCfUfGfUmU mAfCmCfAmCfCmUfAmGfAmAfC mCmUmAmGmGmUmGmGmU mAfGmGfGmCfAmAmUmU 17349 17634 DGAT2_93 mCmUmGmUmUmCfUfAfGmG mUfAmGfCmCfAmCfCmAfCmCfU mUmGmGmUmGmGmCmUmA mAfG mAf AmCfAmG m U mU 17350 17635 DGAT2_94 mUmCmAmUmGmUfAfCfAmU mGfUmGfCmAfGmAfAmUfAmUfG mAmUmUmCmUmGmCmAmC mUfAmCfAmUfGmAmUmU 17351 17636 DGAT2_95 mCmUmGmGmCmAfAfGfAmA mGfUmGfAmCfUmGfCmAfUmUfC mUmGmCmAmGmUmCmAmC mUfUmGfCmCfAmGmUmU 17352 17637 DGAT2_96 mUmGmAmCmCmAfCfCfAmG mAfU mAfU mAfGmUfUmCfCmUfG mGmAmAmCmUmAmUmAmU mGfUmGfGmUfCmAmUmU 17353 17638 DGAT2_97 mCmUmGmUmGmUfUfGfAmG mAfGmGfUmAfCmUfCmCfCmUfC mGmGmAmGmUmAmCmCmU mAf AmCf AmCfAmG m U mU 17354 17639 DGAT2_98 mUmUmUmCmAmAfAfGfAmA mCfCmAfCmUfCmCfCmAfUmUfC mUmGmGmGmAmGmUmGmG mUfUmUfGmAfAmAmUmU 17355 17640 DGAT2_99 mGmUmAmCmAmAfGfCfAmG mGfAmAfGmAfUmCfAmCfCmUfG mGmUmGmAmUmCmUmUmC mCfUmUfGmUfAmCmUmU 17356 17641 DGAT2_10 mCmUmGmAmUmGfUfCfUmG mAfGmAfUmAfCmCfUmCfCmAfG 0 mGmAmGmGmUmAmUmCmU mAfC mAf U mCfAmG m U mU 17357 17642 DGAT2_10 mCmUmUmUmUmGfUfAfUmA mUfUmCfAmAfGmGfC mAfU mAfU 1 mUmGmCmCmUmUmGmAmA mAfC mAf Am AfAm G m U m U 17358 17643 DGAT2_10 mU mAmG mG m U mGfGfAfG mU mAfAmAfCmCfAmGfUmUfAmCfU 2 mAmAmCmUmGmGmUmUmU mCfCmAfCmCfUmAmUmU 17359 17644 DGAT2_10 mG mC mU mAmG mGf UfGfG mA mAfCmCfAmGfUmUfAmCfUmCfC 3 mGmUmAmAmCmUmGmGmU mAfC mCf U mAfG mC m U mU

[0762]

[0763] 17360 17645 DGAT2_10 mGmGmAmGmUmGfGfCfAmA mAfUmGfAmUfAmGfCmAfUmUfG 4 mUmGmCmUmAmUmCmAmU mCfCmAfCmUfCmCmUmU 17361 17646 DGAT2_10 mUmUmAmCmCmUfGfGfCmU mUfGmCfCmAfGmUfGmUfAmGfC 5 mAmCmAmCmUmGmGmCmA mCfAmGfGmUfAmAmUmU 17362 17647 DGAT2_10 mUmUmUmCmUmUfGfGfGmU mUfCmAfUmCfAmGfCmCfAmCfC 6 mGmGmCmUmGmAmUmGmA mCfAmAfG mAf AmAm U mU 17363 17648 DGAT2_10 mC m U mAmG mG mUfGfGf U mG mAfGmAfUmUfUmAfGmCfCmAfC 7 mGmCmUmAmAmAmUmCmU mCfAmCfCmUfAmGmUmU 17364 17649 DGAT2_10 mUmCmGmUmCmUfAfGfUmC mCfAmGfUmUfUmCfAmGfGmAfC 8 mC m U mG mAm AmAmC m U mG mUfAmGfAmCfGmAmUmU 17365 17650 DGAT2_10 mUmCmUmGmUmUfAfUfCmU mCfUmCfAmUfCmAfAmGfAmGfA 9 mCmUmUmGmAmUmGmAmG mUfAmAfCmAfGmAmUmU 17366 17651 DGAT2_11 mCmUmCmAmUmGfUfAfCmA mUfGmCfAmGfAmAfUmAfUmGfU 0 mUmAmUmUmCmUmGmCmA mAfC mAf U mGfAmGmUmU 17367 17652 DGAT2_11 mU mCmU mAmG mGfUfGfG mU mGfAmUfUmUfAmGfCmCfAmCfC 1 mGmGmCmUmAmAmAmUmC mAfC mCf U mAfG mAm U mU 17368 17653 DGAT2_11 mC m AmG m U mAmGfUfAfG mG mUfUmCfCmAfGmAfUmGfCmCfU 2 mCmAmUmCmUmGmGmAmA mAfC mUf AmCfU mG m U mU 17369 17654 DGAT2_11 mGmCmUmGmGmUfGfUfUmU mGfUmUfCmCfAmGfUmCfAmAfA 3 mGmAmCmUmGmGmAmAmC mCfAmCfC mAfG mC m U mU 17370 17655 DGAT2_11 mUmUmAmCmCmUfUfCfCmC mUfAmGfGmAfUmCfUmGfGmGf 4 mCmAmGmAmUmCmCmUmA GmAfAmGfGmUfAmAmUmU 17371 17656 DGAT2_11 mU mG mG mC m U mGf AfUfG mA mGfCmAfUmCfCmAfUmGfUmCfA 5 mCmAmUmGmGmAmUmGmC mUfCmAfGmCfCmAmUmU 17372 17657 DGAT2_11 mGmCmCmUmCmAfCfUfUmU mAfG mGfC mAfC mAfG m AfAm AfA 6 mUmCmUmGmUmGmCmCmU mGfUmGfAmGfGmCmUmU 17373 17658 DGAT2_11 mGmUmUmCmCmAfGfAfAmA mAfCmCfAmAfUmGfUmAfUmUfU 7 mUmAmCmAmUmUmGmGmU mCf U mGfG mAf AmC m U mU 17374 17659 DGAT2_11 mUmUmGmGmGmUfGfGfCmU mCfAmUfGmUfCmAfUmCfAmGfC 8 mGmAmUmGmAmCmAmUmG mCfAmCfCmCfAmAmUmU 17375 17660 DGAT2_11 mGmCmAmGmUmAfGfUfAmG mUfCmCfAmGfAmUfGmCfCmUfA 9 mGmCmAmUmCmUmGmGmA mCfUmAfCmUfGmCmUmU 17376 17661 DGAT2_12 mG mU mAmC mAm UfAfUf U mC mAfUmCfAmGfUmGfCmAfGmAfA 0 mUmGmCmAmCmUmGmAmU mUfAmUfGmUfAmCmUmU 17377 17662 DGAT2_12 mUmCmCmCmCmAfGfAfUmC mAfGmAfAmUfCmUfAmGfGmAfU 1 mCmUmAmGmAmUmUmCmU mCfUmGfGmGfGmAmUmU 17378 17663 DGAT2_12 mG mAmAmG mU m UfCfCf AmG mAfAmUfGmUfAmUfUmUfCmUfG 2 mAm AmAmU m AmC mAm U mU mGfAmAfCmUfUmCmUmU 17379 17664 DGAT2_12 mUmUmUmCmGmAfGfAfCmU mUfGmGfGmAfAmAfGmUfAmGfU 3 mAmCmUmUmUmCmCmCmA mCfU mCfG mAf AmAm U mU 17380 17665 DGAT2_12 mUmUmCmCmCmCfAfGfAmU mGfAmAfUmCfUmAfGmGfAmUfC 4 mCmCmUmAmGmAmUmUmC mUfGmGfGmGfAmAmUmU 17381 17666 DGAT2_12 mGmGmUmGmGmCfUfGfAmU mAfUmCfCmAfUmGfUmCfAmUfC 5 mGmAmCmAmUmGmGmAmU mAfG mCfC mAfC mC m U mU 17382 17667 DGAT2_12 mGmUmGmUmAmCfAfAfGmC mAfGmAfUmCfAmCfCmUfGmCfU 6 mAmGmGmUmGmAmUmCmU mUfGmUfAmCfAmCmUmU 17383 17668 DGAT2_12 mGmCmAmCmUmGfAfUfUmG mAfUmGfAmGfCmCfAmGfCmAfA 7 mCmUmGmGmCmUmCmAmU mUfCmAfGmUfGmCmUmU 17384 17669 DGAT2_12 mUmGmCmUmGmAfCfCfAmC mUfAmGfUmUfCmCfUmGfGmUf 8 mCmAmGmGmAmAmCmUmA GmGfUmCfAmGfCmAmUmU 17385 17670 DGAT2_12 mGmGmGmAmGmUfGfGfCmA mUfGmAfUmAfGmCfAmUfUmGfC 9 mAmUmGmCmUmAmUmCmA mCfAmCfUmCfCmCmUmU 17386 17671 DGAT2_13 mGmCmAmAmUmGfCfUfAmU mAfCmGfAmUfGmAfUmGfAmUfA 0 mCmAmUmCmAmUmCmGmU mGfCmAfUmUfGmCmUmU 17387 17672 DGAT2_13 mG mC mC mAm U mCfCfUfC mA mAfUmAfUmGfUmAfCmAfUmGfA 1 mUmGmUmAmCmAmUmAmU mGfGmAfUmGfGmCmUmU 17388 17673 DGAT2_13 mUmUmUmGmGmAfGfAfGmA mAfCmAfCmUfUmCfAmUfUmCfU 2 mAmUmGmAmAmGmUmGmU mCfUmCfCmAfAmAmUmU 17389 17674 DGAT2_13 mGmAmGmUmGmGfCfAfAmU mGfAmUfGmAfUmAfGmCfAmUfU 3 mGmCmUmAmUmCmAmUmC mGfCmCfAmCfUmCmUmU 17390 17675 DGAT2_13 mGmAmAmCmAmCfAfCfCmC mAfCmCfUmUfUmCfUmUfGmGfG 4 mAmAmGmAmAmAmGmGmU mUfGmUfGmUfUmCmUmU 17391 17676 DGAT2_13 mCmAmUmUmGmCfAfCfCmA mAfGmUfCmUfGmAfCmAfUmGfG 5 mUmGmUmCmAmGmAmCmU mUfG mCf AmAfU mG m U mU 17392 17677 DGAT2_13 mCmUmUmGmGmCfUfGfGmU mCfAmGfUmCfAmAfAmCfAmCfC

[0764]

[0765] 6 mGmUmUmUmGmAmCmUmG mAfG mCfC mAf AmG m U mU 17393 17678 DGAT2_13 mGmUmCmCmAmGfAfAfGmA mUfCmUfGmGfAmAfCmUfUmCfU 7 mAmGmUmUmCmCmAmGmA mUfCmUfGmGfAmCmUmU 17394 17679 DGAT2_13 mCmCmCmUmAmGfUfCfAmC mCfCmGfAmUfAmUfGmAfGmUfG 8 mUmCmAmUmAmUmCmGmG mAfC mUf AmGfG mG m U mU 17395 17680 DGAT2_13 mUmGmGmAmAmCfAfCfAmC mCfUmUfUmCfUmUfGmGfGmUf 9 mCmCmAmAmGmAmAmAmG GmUfGmUfUmCfCmAmUmU 17396 17681 DGAT2_14 mGmUmGmCmUmCfUfAfCmU mGfCmCfAmAfGmUfGmAfAmGfU 0 mUmCmAmCmUmUmGmGmC mAfG mAfG mCfAmCmUmU 17397 17682 DGAT2_14 mCmUmAmCmUmUfCfAfCmU mCfAmCfCmAfGmCfCmAfAmGfU 1 mUmGmGmCmUmGmGmUmG mGfAmAfGmUfAmGmUmU 17398 17683 DGAT2_14 mGmGmUmG m AmAfGfAfC mA mCfAmGfGmUfUmGfUmGfUmGf 2 mCmAmCmAmAmCmCmUmG UmCfUmUfCmAfCmCmUmU 17399 17684 DGAT2_14 mUmGmUmUmGmAfGfGfGmA mAfUmCfAmGfGmUfAmCfUmCfC 3 mGmUmAmCmCmUmGmAmU mCfUmCfAmAfCmAmUmU 17400 17685 DGAT2_14 mGmGmCmUmCmAfGfCfUmA mAfAmGfAmGfAmGfGmUfUmAfG 4 mAmCmCmUmCmUmCmUmU mCfUmGfAmGfCmCmUmU 17401 17686 DGAT2_14 mUmUmGmCmCmAfUfUfAmG mUfCmCfAmAfGmUfCmAfCmUfA 5 mUmGmAmCmUmUmGmGmA mAf U mGfG mCf AmAm U mU 17402 17687 DGAT2_14 mCmAmAmCmCmCfUfCfUmC mAfAmCfAmCfAmCfAmGfGmAfG 6 mCmUmGmUmGmUmGmUmU mAfGmGfGmUfUmGmUmU 17403 17688 DGAT2_14 mGmAmGmCmUmAfGfGfUmG mCfAmGfUmUfAmCfUmCfCmAfC 7 mGmAmGmUmAmAmCmUmG mCf U mAfG mCfUmCmUmU 17404 17689 DGAT2_14 mUmAmUmUmCmUfGfCfAmC mCfAmGfCmAfAmUfCmAfGmUfG 8 mUmGmAmUmUmGmCmUmG mCfAmGfAmAfUmAmUmU 17390 17675 DGAT2_14 mGmAmAmCmAmCfAfCfCmC mAfCmCfUmUfUmCfUmUfGmGfG 9 mAmAmGmAmAmAmGmGmU mUfGmUfGmUfUmCmUmU 17405 17690 DGAT2_15 mGmUmGmGmGmUfUfAfUmU mUfUmUfCmUfUmUfUmAfAmAfU 0 mU m AmAmAm AmG mAm AmA mAfAmCfCmCfAmCmUmU 17406 17691 DGAT2_15 mC m AmG m U mU m UfAfCfC mU mAfUmCfU mGfG mGfG mAfAmGf 1 mUmCmCmCmCmAmGmAmU G m UfAmAf AmCfU mG m U mU 17407 17692 DGAT2_15 mCmCmAmGmUmUfUfGfAmU mAfGmAfAmGfGmGfAmGfAmUfC 2 mCmUmCmCmCmUmUmCmU mAf AmAfC mUfG mG m U mU 17408 17693 DGAT2_15 mGmAmGmAmCmUfAfCfUmU mUfGmGfAmUfGmGfGmAfAmAfG 3 mUmCmCmCmAmUmCmCmA mUfAmGfUmCfUmCmUmU 17409 17694 DGAT2_15 mCmAmCmCmCmCfUfAfGmU mAfUmAfUmGfAmGfUmGfAmCfU 4 mCmAmCmUmCmAmUmAmU mAfGmGfGmGfUmGmUmU 17410 17695 DGAT2_15 mCmUmUmCmCmCfCfAfGmA mAfAmUfCmUfAmGfG mAfUmCfU 5 mUmCmCmUmAmGmAmUmU mGfGmGfGmAfAmGmUmU 17411 17696 DGAT2_15 mGmGmCmUmAmAfAfUfCmU mAfUmUfAmGfGmCfCmCfAmGfA 6 mGmGmGmCmCmUmAmAmU mUfUmUfAmGfCmCmUmU 17412 17697 DGAT2_15 mC m U mAm AmAmUfCfUfG mG mAfGmAfUmUfAmGfGmCfCmCfA 7 mGmCmCmUmAmAmUmCmU mGfAmUfUmUfAmGmUmU 17413 17698 DGAT2_15 mCmUmUmUmAmUfUfGfCmC mUfGmGfGmGfUmAfGmUfGmGf 8 mAmCmUmAmCmCmCmCmA CmAfAmUfAmAfAmGmUmU 17414 17699 DGAT2_15 mC m U mC mAm U mAfCf AfAmG mAfUmAfAmAfGmGfGmGfCmUfU 9 mCmCmCmCmUmUmUmAmU mGfUmAfUmGfAmGmUmU 17415 17700 DGAT2_16 mCmUmUmCmUmCfAfUfAmC mAfAmGfGmGfGmCfUmUfGmUfA 0 mAmAmGmCmCmCmCmUmU mUfG mAfG mAf AmG m U mU 17416 17701 DGAT2_16 mCmGmGmCmUmUfCfCfCmG mAfC mGfGmCfCmCfCmGfCmGf 1 mCmGmGmGmGmCmCmGmU GmGfAmAfGmCfCmGmUmU 17417 17702 DGAT2_16 mGmCmUmUmCmCfCfGfCmG mUfCmAfCmGfGmCfCmCfCmGfC 2 mGmGmGmCmCmGmUmGmA mGfGmGfAmAfGmCmUmU 17418 17703 DGAT2_16 mGmGmCmCmGmUfGfAfCmU mAfGmCfCmCfGmCfCmCfAmGfU 3 mGmGmGmCmGmGmGmCmU mCfAmCfGmGfCmCmUmU 17419 17704 DGAT2_16 mGmCmCmGmUmGfAfCfUmG mAf AmGfC mCfC mGfC mCfC mAfG 4 mGmGmCmGmGmGmCmUmU mUfCmAfCmGfGmCmUmU 17420 17705 DGAT2_16 mCmGmUmGmAmCfUfGfGmG mUfGmAfAmGfCmCfCmGfCmCfC 5 mCmGmGmGmCmUmUmCmA mAfGmUfCmAfCmGmUmU 17421 17706 DGAT2_16 mC m U mG mG mG mCfGfGfG mC mAfUmGfGmCfUmGfAmAfGmCfC 6 mUmUmCmAmGmCmCmAmU mCfG mCfC mCf AmG m U mU 17422 17707 DGAT2_16 mGmGmGmCmGmGfGfCfUmU mUfCmAfUmGfGmCfUmGfAmAfG 7 mCmAmGmCmCmAmUmGmA mCfCmCfGmCfCmCmUmU 17423 17708 DGAT2_16 mGmGmCmGmGmGfCfUfUmC mUfUmCfAmUfGmGfCmUfGmAfA 8 mAmG mC mC mAm U mG m AmA mGfCmCfCmGfCmCmUmU

[0766]

[0767] 17424 17709 DGAT2_16 mCmGmGmGmAmCfAfCfCmA mAfAmUfAmGfUmCfUmAfUmGfG 9 mUmAmGmAmCmUmAmUmU mUfGmUfCmCfCmGmUmU 17425 17710 DGAT2_17 mGmGmGmAmCmAfCfCfAmU mAfAmAfUmAfGmUfCmUfAmUfG 0 mAmGmAmCmUmAmUmUmU mGfUmGfUmCfCmCmUmU 17426 17711 DGAT2_17 mGmCmUmUmUmCfAfAfAmG mAfCmUfCmCfCmAfUmUfCmUfU 1 mAmAmUmGmGmGmAmGmU mUfGmAfAmAfGmCmUmU 17427 17712 DGAT2_17 mGmGmGmUmUmAfUfUfUmA mAfAmUfUmUfCmUfUmUfUmAfA 2 mAm AmAmG m AmAmAm U mU mAf U mAf AmCfC mC mU mU 17428 17713 DGAT2_17 mCmUmUmCmUmUfCfCfCmU mAfCmUfUmCfAmGfGmAfAmGfG 3 mUmCmCmUmGmAmAmGmU mGfAmAfG mAf AmG m U mU 17429 17714 DGAT2_17 mCmCmCmUmUmCfCfUfGmA mUfUmUfGmUfCmAfCmUfUmCfA 4 mAmGmUmGmAmCmAmAmA mGfGmAfAmGfGmGmUmU 17430 17715 DGAT2_17 mCmAmGmUmCmUfUfCfUmU mUfUmCfUmUfCmCfCmCfAmAfG 5 mG mG mG mG mAm AmG m AmA mAf AmGf AmCfU mG m U mU 17431 17716 DGAT2_17 mCmUmUmCmUmUfGfGfGmG mAfUmCfCmUfUmCfUmUfCmCfC 6 mAmAmGmAmAmGmGmAmU mCfAmAfGmAfAmGmUmU 17432 17717 DGAT2_17 mGmAmUmUmCmAfCfUfUmU mUfAmGfGmGfGmCfAmAfAmAfA 7 mUmUmGmCmCmCmCmUmA mGfUmGfAmAfUmCmUmU 17433 17718 DGAT2_17 mGmUmUmUmUmUfCfUfUmG mUfCmAfGmCfCmAfCmCfCmAfA 8 mGmGmUmGmGmCmUmGmA mGfAmAf AmAf AmC m U mU 17434 17719 DGAT2_17 mG mAmAmC mC mCfAfAfG mC mAfAmAfAmGfUmGfAmGfGmCfU 9 mCmUmCmAmCmUmUmUmU mUfGmGfGmUfUmCmUmU 17435 17720 DGAT2_18 mCmUmCmUmUmCfUfUfCmC mUfUmCfAmGfGmAfAmGfGmGfA 0 mCmUmUmCmCmUmGmAmA mAfG mAf AmGf AmG m U mU 17368 17653 DGAT2_18 mC m AmG m U mAmGfUfAfG mG mUfUmCfCmAfGmAfUmGfCmCfU 1 mCmAmUmCmUmGmGmAmA mAfC mUf AmCfU mG m U mU 17370 17655 DGAT2_18 mUmUmAmCmCmUfUfCfCmC mUfAmGfGmAfUmCfUmGfGmGf 2 mCmAmGmAmUmCmCmUmA GmAfAmGfGmUfAmAmUmU 17373 17658 DGAT2_18 mGmUmUmCmCmAfGfAfAmA mAfCmCfAmAfUmGfUmAfUmUfU 3 mUmAmCmAmUmUmGmGmU mCf U mGfG mAf AmC m U mU 17376 17661 DGAT2_18 mG mU mAmC mAm UfAfUf U mC mAfUmCfAmGfUmGfCmAfGmAfA 4 mUmGmCmAmCmUmGmAmU mUfAmUfGmUfAmCmUmU 17377 17662 DGAT2_18 mUmCmCmCmCmAfGfAfUmC mAfGmAfAmUfCmUfAmGfGmAfU 5 mCmUmAmGmAmUmUmCmU mCfUmGfGmGfGmAmUmU 17378 17663 DGAT2_18 mG mAmAmG mU m UfCfCf AmG mAfAmUfGmUfAmUfUmUfCmUfG 6 mAm AmAmU m AmC mAm U mU mGfAmAfCmUfUmCmUmU 17379 17664 DGAT2_18 mUmUmUmCmGmAfGfAfCmU mUfGmGfGmAfAmAfGmUfAmGfU 7 mAmCmUmUmUmCmCmCmA mCfU mCfG mAf AmAm U mU 17382 17667 DGAT2_18 mGmUmGmUmAmCfAfAfGmC mAfGmAfUmCfAmCfCmUfGmCfU 8 mAmGmGmUmGmAmUmCmU mUfGmUfAmCfAmCmUmU 17385 17670 DGAT2_18 mGmGmGmAmGmUfGfGfCmA mUfGmAfUmAfGmCfAmUfUmGfC 9 mAmUmGmCmUmAmUmCmA mCfAmCfUmCfCmCmUmU 17386 17671 DGAT2_19 mGmCmAmAmUmGfCfUfAmU mAfCmGfAmUfGmAfUmGfAmUfA 0 mCmAmUmCmAmUmCmGmU mGfCmAfUmUfGmCmUmU 17387 17672 DGAT2_19 mG mC mC mAm U mCfCfUfC mA mAfUmAfUmGfUmAfCmAfUmGfA 1 mUmGmUmAmCmAmUmAmU mGfGmAfUmGfGmCmUmU 17391 17676 DGAT2_19 mCmAmUmUmGmCfAfCfCmA mAfGmUfCmUfGmAfCmAfUmGfG 2 mUmGmUmCmAmGmAmCmU mUfG mCf AmAfU mG m U mU 17393 17678 DGAT2_19 mGmUmCmCmAmGfAfAfGmA mUfCmUfGmGfAmAfCmUfUmCfU 3 mAmGmUmUmCmCmAmGmA mUfCmUfGmGfAmCmUmU 17399 17684 DGAT2_19 mUmGmUmUmGmAfGfGfGmA mAfUmCfAmGfGmUfAmCfUmCfC 4 mGmUmAmCmCmUmGmAmU mCfUmCfAmAfCmAmUmU 17402 17687 DGAT2_19 mCmAmAmCmCmCfUfCfUmC mAfAmCfAmCfAmCfAmGfGmAfG 5 mCmUmGmUmGmUmGmUmU mAfGmGfGmUfUmGmUmU 17436 17721 DGAT2_19 mCmUmUmCmAmCfUfUfGmG mAfAmAfCmAfCmCfAmGfCmCfA 6 mCmUmGmGmUmGmUmUmU mAfG mUfG mAf AmG m U mU 17437 17722 DGAT2_19 mCmUmCmGmUmCfUfAfGmU mAfGmUfUmUfCmAfGmGfAmCfU 7 mCmCmUmGmAmAmAmCmU mAfG mAfC mGfAmGmUmU 17438 17723 DGAT2_19 mG mAmG mC m AmGfCfAfG mA mUfGmGfAmAfCmUfAmAfUmCfU 8 mUmUmAmGmUmUmCmCmA mGfCmUfGmCfUmCmUmU 17439 17724 DGAT2_19 mG mAmG mG mG mAfGfUf AmC mAfG mAfC mAfUmCfAmGfGmUfA 9 mCmUmGmAmUmGmUmCmU mCfUmCfCmCfUmCmUmU 17440 17725 DGAT2_20 mC mUmG mAmC mCfUfGfG mU mUfAmGfAmUfGmGfGmAfAmCfC 0 mUmCmCmCmAmUmCmUmA mAfG mGfU mCf AmG m U mU 17441 17726 DGAT2_20 mG mAmC mU mG mGf AfAfC mA mUfCmUfU mGfG mGfU mGfUmGf

[0768]

[0769] 1 mCmAmCmCmCmAmAmGmA UmUfCmCfAmGfUmCmUmU 17442 17727 DGAT2_20 mU mUmG mAmG mGfGfAfG mU mAfCmAfUmCfAmGfGmUfAmCfU 2 mAmCmCmUmGmAmUmGmU mCfC mCf U mCf AmAm U mU 17443 17728 DGAT2_20 mGmCmAmAmGmAfAfUfGmC mAfGmGfGmUfGmAfCmUfGmCfA 3 mAmGmUmCmAmCmCmCmU mUfUmCfUmUfGmCmUmU 17444 17729 DGAT2_20 mG mAmAm U mG mGfGfAfG mU mAfGmCfAmUfUmGfCmCfAmCfU 4 mGmGmCmAmAmUmGmCmU mCfCmCfAmUfUmCmUmU 17445 17730 DGAT2_20 mG mAmAmUmG mCfCfUfG mU mUfCmCfCmUfCmAfAmCfAmCfA 5 mGmUmUmGmAmGmGmGmA mGfGmCfAmUfUmCmUmU 17446 17731 DGAT2_20 mUmUmCmGmAmGfAfCfUmA mAfUmGfGmGfAmAfAmGfUmAfG 6 mCmUmUmUmCmCmCmAmU mUfCmUfCmGfAmAmUmU 17447 17732 DGAT2_20 mCmUmUmUmCmGfAfGfAmC mGfGmGfAmAfAmGfUmAfGmUfC 7 mUmAmCmUmUmUmCmCmC mUfCmGfAmAfAmGmUmU 17448 17733 DGAT2_20 mC mAmAmGmG mGfCfUfU mU mCfAmGfUmUfUmCfAmCfAmAfA 8 mG m U mG m AmAmAmC m U mG mGfCmCfCmUfUmGmUmU 17449 17734 DGAT2_20 mCmAmAmUmUmUfUfGfCmU mUfAmAfUmGfGmUfUmUfAmGfC 9 mAm AmAmC mC mAmU m U mA mAfAmAfAmUfUmGmUmU 17450 17735 DGAT2_21 mC mAmG m AmC m UfUfUf U mG mAfGmGfCmAfUmAfUmAfCmAfA 0 mUmAmUmAmUmGmCmCmU mAf AmGf U mCfUmGmUmU 17451 17736 DGAT2_21 mGmAmAmAmGmCfCfAfCmU mUfGmUfAmUfGmAfGmAfAmGfU 1 mUmCmUmCmAmUmAmCmA mGfGmCfUmUfUmCmUmU 17452 17737 DGAT2_21 mCmAmGmGmAmAfCfUfAmU mUfCmCfAmAfAmGfAmUfAmUfA 2 mAmUmCmUmUmUmGmGmA mGfUmUfCmCfUmGmUmU 17453 17738 DGAT2_21 mCmAmUmGmAmGfCfUfAmG mUfUmAfCmUfCmCfAmCfCmUfA 3 mGmUmGmGmAmGmUmAmA mGfCmUfCmAfUmGmUmU 17454 17739 DGAT2_21 mCmAmUmGmUmAfCfAfUmA mAfGmUfGmCfAmGfAmAfUmAfU 4 mUmUmCmUmGmCmAmCmU mGfUmAfCmAfUmGmUmU 17455 17740 DGAT2_21 mCmGmCmUmAmCfUfUfUmC mAfGmUfAmGfUmCfUmCfGmAfA 5 mG mAmG mAmC m U mAmC mU mAfG mUf AmGfC mG m U mU 17456 17741 DGAT2_21 mCmUmUmCmUmGfCfAfAmC mUfGmUfGmCfUmGfAmAfGmUfU 6 mUmUmCmAmGmCmAmCmA mGfC mAfG mAf AmG m U mU 17457 17742 DGAT2_21 mCmAmCmCmAmUfGfUfCmA mAfCmAfAmAfAmGfUmCfUmGfA 7 mGmAmCmUmUmUmUmGmU mCf AmUfG mGf U mG m U mU 17458 17743 DGAT2_21 mC m U mU mG mAm AfAfAf U mA mAfCmUfUmUfCmAfUmUfUmAfU 8 mAmAmUmGmAmAmAmGmU mUfUmUfCmAfAmGmUmU 17459 17744 DGAT2_21 mG mCmC mGmAmUfGfGfG mU mUfUmCfUmUfCmUfGmGfAmCfC 9 mCmCmAmGmAmAmGmAmA mCfAmUfCmGfGmCmUmU 17460 17745 DGAT2_22 mGmGmUmCmAmCfAfGfUmG mUfUmUfCmGfGmAfCmCfCmAfC 0 mGmGmUmCmCmGmAmAmA mUfGmUfGmAfCmCmUmU 17461 17746 DGAT2_22 mUmGmUmGmGmGfUfUfAmU mUfUmCfUmUfUmUfAmAfAmUfA 1 mU m U mAmAm AmAmG m AmA mAfCmCfCmAfCmAmUmU 17462 17747 DGAT2_22 mUmUmGmAmCmUfGfGfAmA mUfUmGfGmGfUmGfUmGfUmUf 2 mCmAmCmAmCmCmCmAmA CmCfAmGfUmCfAmAmUmU 17463 17748 DGAT2_22 mCmGmAmAmCmCfCfAfAmG mAfAmAfGmUfGmAfGmGfCmUfU 3 mCmCmUmCmAmCmUmUmU mGfGmGfUmUfCmGmUmU 17464 17749 DGAT2_22 mAm AmAmG mAmAf UfGfG mG mAfUmUfGmCfCmAfCmUfCmCfC 4 mAmGmUmGmGmCmAmAmU mAfUmUfCmUfUmUmUmU 17465 17750 DGAT2_22 mUmUmUmAmCmCfUfUfCmC mAfGmGfAmUfCmUfGmGfGmGf 5 mCmCmAmGmAmUmCmCmU AmAfG mGfU mAf AmAm U mU 17466 17751 DGAT2_22 mCmAmGmUmUmUfGfAfUmC mCfAmGfAmAfGmGfGmAfGmAfU 6 mUmCmCmCmUmUmCmUmG mCfAmAf AmCfU mG m U mU 17467 17752 DGAT2_22 mUmCmAmCmCmCfCfUfAmG mUfAmUfGmAfGmUfGmAfCmUfA 7 mUmCmAmCmUmCmAmUmA mGfGmGfG mUfG mAmU mU 17468 17753 DGAT2_22 mUmCmAmGmUmUfUfAfCmC mUfCmUfGmGfGmGfAmAfGmGf 8 mUmUmCmCmCmCmAmGmA U m AfAmAfC mUfG mAm U mU 17469 17754 DGAT2_22 mCmCmUmAmGmGfGfAfUmG mUfUmCfGmCfCmUfCmUfCmAfU 9 mAmGmAmGmGmCmGmAmA mCfC mCf U mAfG mG m U mU 17470 17755 DGAT2_23 mAmCmUmCmAmGfUfCfUmU mUfUmCfCmCfCmAfAmGfAmAfG 0 mCmUmUmGmGmGmGmAmA mAfCmUfGmAfGmUmUmU 17471 17756 DGAT2_23 mUmUmUmGmAmUfCfUfCmC mUfGmGfCmAfGmAfAmGfGmGfA 1 mCmUmUmCmUmGmCmCmA mGfAmUfCmAfAmAmUmU 17472 17757 DGAT2_23 mU mG mG mC m U mAf AfAfU mC mUfUmAfGmGfCmCfCmAfGmAfU 2 mUmGmGmGmCmCmUmAmA mUfUmAfGmCfCmAmUmU 17473 17758 DGAT2_23 mGmUmGmGmCmUfAfAfAmU mUfAmGfGmCfCmCfAmGfAmUfU 3 mCmUmGmGmGmCmCmUmA mUfAmGfCmCfAmCmUmU

[0770]

[0771] 17474 17759 DGAT2_23 mG mAmG mC m U mGf AfCfC mU mAf U mGfG mGf AmAfC mCfAmGfG 4 mGmGmUmUmCmCmCmAmU mUfCmAfGmCfUmCmUmU 17475 17760 DGAT2_23 mGmAmAmAmCmUfCfAfGmU mCfCmCfAmAfGmAfAmGfAmCfU 5 mCmUmUmCmUmUmGmGmG mGfAmGfUmUfUmCmUmU 17476 17761 DGAT2_23 mGmGmAmGmGmUfAfUfCmU mUfGmAfCmAfGmGfGmCfAmGfA 6 mGmCmCmCmUmGmUmCmA mUfAmCfCmUfCmCmUmU 17477 17762 DGAT2_23 mUmUmUmGmAmCfUfGfGmA mUfGmGfGmUfGmUfGmUfUmCf 7 mAmCmAmCmAmCmCmCmA CmAfGmUfCmAfAmAmUmU 17478 17763 DGAT2_23 mGmCmCmU mAm AfUfCf U mG mUfG mAfG mCfC mAfC mCfC m AfG 8 mGmGmUmGmGmCmUmCmA mAf U mUf AmGfG mC m U mU 17479 17764 DGAT2_23 mGmCmCmGmGmGfAfCfAmC mUfAmGfUmCfUmAfUmGfGmUfG 9 mCmAmUmAmGmAmCmUmA mUfCmCfCmGfGmCmUmU 17480 17765 DGAT2_24 mAm AmU mG mG mGfAfGf U mG mUfAmGfCmAfUmUfGmCfCmAfC 0 mGmCmAmAmUmGmCmUmA mUfCmCfCmAfUmUmUmU 17481 17766 DGAT2_24 mGmCmAmGmGmAfGfGfUmC mAfCmCfCmAfCmUfGmUfGmAfC 1 mAmCmAmGmUmGmGmGmU mCfUmCfCmUfGmCmUmU 17482 17767 DGAT2_24 mG mG mC mC mG m AfUfGfG mG mUfCmUfUmCfUmGfGmAfCmCfC 2 mUmCmCmAmGmAmAmGmA mAf U mCfGmGfCmCmUmU 17483 17768 DGAT2_24 mGmGmAmGmCmAfCfCfCmA mUfUmGfCmUfGmGfGmUfUmGf 3 mAmCmCmCmAmGmCmAmA GmGfUmGfCmUfCmCmUmU 17484 17769 DGAT2_24 mGmGmCmUmGmGfUfGfCmC mUfUmGfGmAfGmUfAmGfGmGf 4 mCmUmAmCmUmCmCmAmA CmAfCmCfAmGfCmCmUmU 17485 17770 DGAT2_24 mAmCmUmGmGmAfAfCfAmC mUfUmCfUmUfGmGfGmUfGmUf 5 mAmCmCmCmAmAmGmAmA GmUfUmCfCmAfGmUmUmU 17486 17771 DGAT2_24 mCmUmGmCmUmGfGfGfGmU mAfCmAfGmCfCmUfAmGfAmCfC 6 mCmUmAmGmGmCmUmGmU mCfC mAfG mCfAmGmUmU 17487 17772 DGAT2_24 mCmUmGmGmGmUfGfCfCmU mAfGmUfUmGfCmAfGmAfAmGfG 7 mUmCmUmGmCmAmAmCmU mCfAmCfCmCfAmGmUmU 17488 17773 DGAT2_24 mAm U mAmC mAm UfUfGfG mU mUfGmGfGmGfCmGfAmAfAmCfC 8 mUmUmCmGmCmCmCmCmA mAfAmUfGmUfAmUmUmU 17489 17774 DGAT2_24 mG mC mU m AmAm AfUfCf U mG mGfAmUfU mAfG mGfCmCfC mAfG 9 mGmGmCmCmUmAmAmUmC mAfUmUfUmAfGmCmUmU 17490 17775 DGAT2_25 mGmGmGmCmCmUfAfAfUmC mAfG mC fC m AfC mC fC mAfG m Af U 0 mUmGmGmGmUmGmGmCmU mUfAmGfGmCfCmCmUmU 17491 17776 DGAT2_25 mG mAmAmAmC mUfGfGfC mC mAfUmGfAmCfGmCfAmGfGmGfC 1 mCmUmGmCmGmUmCmAmU mCfAmGfUmUfUmCmUmU 17492 17777 DGAT2_25 mG mC mC mU mG mGfGfUfG mC mUfUmGfCmAfGmAfAmGfGmCfA 2 mCmUmUmCmUmGmCmAmA mCfC mCf AmGfG mC m U mU 17493 17778 DGAT2_25 mUmCmUmCmAmUfAfCfAmA mUfAmAfAmGfGmGfGmCfUmUfG 3 mGmCmCmCmCmUmUmUmA mUfAmUfGmAfGmAmUmU 17494 17779 DGAT2_25 mCmAmAmGmCmCfCfAfUmC mAfAmCfAmGfUmGfGmUfGmAfU 4 mAmCmCmAmCmUmGmUmU mGfGmGfCmUfUmGmUmU 17495 17780 DGAT2_25 mGmUmCmCmGmAfAfAfCmU mAfC mAfC mAfG mCfC mCfAmGfU 5 mGmGmGmCmUmGmUmGmU mUfUmCfGmGfAmCmUmU 17496 17781 DGAT2_25 mCmCmCmUmAmGfGfGfAmU mUfCmGfCmCfUmCfUmCfAmUfC 6 mGmAmGmAmGmGmCmGmA mCfC mUf AmGfG mG m U mU 17497 17782 DGAT2_25 mAmUmGmGmGmUfGfUfCmU mAfUmAfAmCfCmCfAmCfAmGfA 7 mGmUmGmGmGmUmUmAmU mCfAmCfCmCfAmUmUmU 17498 17783 DGAT2_25 mGmCmUmUmUmGfUfGfAmA mAfGmGfGmCfCmAfGmUfUmUfC 8 mAmCmUmGmGmCmCmCmU mAfC mAf AmAfG mC m U mU 17499 17784 DGAT2_25 mGmGmGmUmGmGfCfUfGmA mUfCmCfAmUfGmUfCmAfUmCfA 9 mUmGmAmCmAmUmGmGmA mGfCmCfAmCfCmCmUmU 17500 17785 DGAT2_26 mCmCmAmAmCmCfCfUfCmU mAfC mAfC mAfC mAfG mGfAmGfA 0 mCmCmUmGmUmGmUmGmU mGfGmGfUmUfGmGmUmU 17501 17786 DGAT2_26 mCmAmGmUmUmGfCfCfCmC mUfC mAfC mAfC mAfAmCfGmGfG 1 mGmUmUmGmUmGmUmGmA mGfC mAf AmCfU mG m U mU 17502 17787 DGAT2_26 mGmGmUmGmGmCfUfAfAmA mAfGmGfCmCfCmAfGmAfUmUfU 2 mUmCmUmGmGmGmCmCmU mAfG mCfC mAfC mC m U mU 17503 17788 DGAT2_26 mAm U mG mG mG m AfGfUfG mG mAfUmAfGmCfAmUfUmGfCmCfA 3 mCmAmAmUmGmCmUmAmU mCfUmCfCmCfAmUmUmU 17504 17789 DGAT2_26 mCmCmUmCmAmCfCfCfCmU mUfGmAfGmUfGmAfCmUfAmGfG 4 mAmGmUmCmAmCmUmCmA mGfGmUfGmAfGmGmUmU 17505 17790 DGAT2_26 mCmCmCmAmAmGfCfUfGmG mUfUmGfGmGfUmGfCmUfCmCf 5 mAmGmCmAmCmCmCmAmA AmGfCmUfUmGfGmGmUmU 17506 17791 DGAT2_26 mG mUmC mUmG mGfAfGfG mU mAfGmGfGmCfAmGfAmUfAmCfC

[0772]

[0773] 6 mAmUmCmUmGmCmCmCmU mUfCmCfAmGfAmCmUmU 17507 17792 DGAT2_26 mAm AmG m U mG m UfCfAf U mG mAfC mAfG mAfC mAfC mCfC m AfU 7 mGmGmUmGmUmCmUmGmU mGfAmCfAmCfUmUmUmU 17508 17793 DGAT2_26 mCmCmCmUmAmCfUfCfCmA mUfGmAfUmGfGmGfCmUfUmGf 8 mAmGmCmCmCmAmUmCmA GmAfGmUfAmGfGmGmUmU 17509 17794 DGAT2_26 mGmGmUmUmUmCfGfCfCmC mAfGmAfUmGfCmAfUmGfGmGf 9 mCmAmUmGmCmAmUmCmU G mCfG m AfAmAfC mC m U mU 17510 17795 DGAT2_27 mGmGmGmCmUmGfUfGfUmG mAfAmGfU mAfG mCfG mCfC mAfC 0 mGmCmGmCmUmAmCmUmU mAfC mAfG mCfCmCmUmU 17511 17796 DGAT2_27 mCmUmCmAmCmCfCfCfUmA mAfUmGfAmGfUmGfAmCfUmAfG 1 mGmUmCmAmCmUmCmAmU mGfGmGfUmGfAmGmUmU 17512 17797 DGAT2_27 mCmCmUmUmCmCfCfCfAmG mAfUmCfUmAfGmGfAmUfCmUfG 2 mAmUmCmCmUmAmGmAmU mGfGmGfAmAfGmGmUmU 17513 17798 DGAT2_27 mGmGmAmGmCmUfGfAfCmC mUfGmGfGmAfAmCfCmAfGmGfU 3 mUmGmGmUmUmCmCmCmA mCf AmGfC mUfC mC m U mU 17514 17799 DGAT2_27 mGmGmGmUmCmCfGfAfAmA mAfCmAfGmCfCmCfAmGfUmUfU 4 mCmUmGmGmGmCmUmGmU mCfG mGfAmCfC mC m U mU 17515 17800 DGAT2_27 mGmCmUmGmGmGfGfUfCmU mAfAmAfCmAfGmCfCmUfAmGfA 5 mAmGmGmCmUmGmUmUmU mCfC mCfC mAfG mC m U mU 17516 17801 DGAT2_27 mGmUmCmAmUmGfGfGfUmG mAfC mCfC mAfC mAfG mAfC mAfC 6 mUmCmUmGmUmGmGmGmU mCfC mAf U mGf AmC m U mU 17517 17802 DGAT2_27 mCmCmGmAmAmCfCfCfAmA mAfAmGfU mGfAmGfGmCfUmUfG 7 mGmCmCmUmCmAmCmUmU mGfGmUfUmCfGmGmUmU 17518 17803 DGAT2_27 mAmCmUmAmCmUfUfUfCmC mAfGmCfUmGfGmAfUmGfGmGf 8 mCmAmUmCmCmAmGmCmU AmAfAmGfUmAfGmUmUmU 17519 17804 DGAT2_27 mCmCmAmAmGmCfCfCfAmU mAfCmAfGmUfGmGfUmGfAmUfG 9 mCmAmCmCmAmCmUmGmU mGfGmCfUmUfGmGmUmU 17520 17805 DGAT2_28 mGmGmGmGmAmGfGfAfAmA mAfGmGfGmUfUmGfGmGfUmUf 0 mCmCmCmAmAmCmCmCmU UmCfCmUfCmCfCmCmUmU 17521 17806 DGAT2_28 mAm AmC m U mC mAfGfUfC mU mUfCmCfCmCfAmAfGmAfAmGfA 1 mUmCmUmUmGmGmGmGmA mCfUmGfAmGfUmUmUmU 17522 17807 DGAT2_28 mCmCmUmC m AmGf UfUfU mA mUfGmGfGmGfAmAfGmGfUmAfA 2 mCmCmUmUmCmCmCmCmA m Af C m Uf G m AfG mG m U m U 17523 17808 DGAT2_28 mCmCmCmAmUmCfCfAfGmC mUfCmUfUmCfAmCfCmAfGmCfU 3 mUmGmGmUmGmAmAmGmA mGfGmAfUmGfGmGmUmU 17524 17809 DGAT2_28 mGmAmGmGmUmCfAfCfAmG mUfCmGfGmAfCmCfCmAfCmUfG 4 mUmGmGmGmUmCmCmGmA mUfGmAfCmCfUmCmUmU 17525 17810 DGAT2_28 mCmUmGmGmAmGfGfUfAmU mAfC mAfG mGfG mCfAmGfAm UfA 5 mCmUmGmCmCmCmUmGmU mCfCmUfCmCfAmGmUmU 17526 17811 DGAT2_28 mCmCmUmAmCmCfUfCfAmC mUfGmAfCmUfAmGfGmGfGmUf 6 mCmCmCmUmAmGmUmCmA GmAfGmGfUmAfGmGmUmU 17527 17812 DGAT2_28 mAmCmCmCmAmAfGfCfCmU mAfGmAfAmAfAmGfUmGfAmGfG 7 mCmAmCmUmUmUmUmCmU mCfUmUfGmGfGmUmUmU 17528 17813 DGAT2_28 mGmGmAmAmCmCfGfCfAmA mAfCmAfAmAfGmCfCmCfUmUfG 8 mGmGmGmCmUmUmUmGmU mCfGmGfUmUfCmCmUmU 17529 17814 DGAT2_28 mCmCmCmGmAmAfCfCfCmA mAfGmUfGmAfGmGfCmUfUmGf 9 mAmGmCmCmUmCmAmCmU GmGfUmUfCmGfGmGmUmU 17530 17815 DGAT2_29 mGmCmUmGmAmCfCfUfGmG mAfGmAfUmGfGmGfAmAfCmCfA 0 mUmUmCmCmCmAmUmCmU mGfGmUfCmAfGmCmUmU 17531 17816 DGAT2_29 mGmUmUmAmGmAfUfGfAmU mAf AmAfAm AfG m UfG mAfAm UfC 1 mUmCmAmCmUmUmUmUmU mAfUmCfUmAfAmCmUmU 17532 17817 DGAT2_29 mG mG mAmAmC m UfAfUf AmU mUfAmUfCmCfAmAfAmGfAmUfA 2 mCmUmUmUmGmGmAmUmA mUfAmGfUmUfCmCmUmU 17533 17818 DGAT2_29 mG mAmC mUmAmUfUfUfG mC mUfCmUfUmUfGmAfAmAfGmCfA 3 mUmUmUmCmAmAmAmGmA mAf AmUf AmGfU mC m U mU 17534 17819 DGAT2_29 mCmUmAmUmUmUfGfCfUmU mAfUmUfCmUfUmUfGmAfAmAfG 4 mUmCmAmAmAmGmAmAmU mCfAmAfAmUfAmGmUmU 17535 17820 DGAT2_29 mG mCmU mAmAmAfCfCfAmU mAf AmCf AmUfU mGfU mAfAm UfG 5 mUmAmCmAmAmUmGmUmU mGfUmUfUmAfGmCmUmU 17536 17821 DGAT2_29 mC m U mAm AmAmCfCfAf U mU mUfAmAfCmAfU mUfG mUfAmAfU 6 mAmCmAmAmUmGmUmUmA mGfGmUfUmUfAmGmUmU 17537 17822 DGAT2_29 mG mG m AmAm AmAf AfGfU mC mUfGmAfAmAfUmAfCmUfGmAfC 7 mAmGmUmAmUmUmUmCmA mUfUmUfUmUfCmCmUmU 17538 17823 DGAT2_29 mG mAmAm AmAmAfGfUfC mA mUfUmGfAmAfAmUfAmCfUmGfA 8 mGmUmAmUmUmUmCmAmA mCfUmUfUmUfUmCmUmU

[0774]

[0775] 17539 17824 DGAT2_29 mGmGmAmGmUmAfAfCfUmG mAf AmGfAm AfAmAf AmCfC mAfG 9 mGmUmUmUmUmUmCmUmU mUfUmAfCmUfCmCmUmU 17540 17825 DGAT2_30 mAmUmAmGmAmCfUfAfUmU mUfUmGfAmAfAmGfCmAfAmAfU

[0776]

[0777] 0 mUmGmCmUmUmUmCmAmA mAfGmUfCmUfAmUmUmU

[0778] Table 18

[0779] SEQ ID Sense APO_B SEQ ID Antisense APO_B ID NOs:

[0780] NOs:

[0781] 18523 ctrl_ApoB CCUGGACAUUCAGAAC 18527 UUCUUGUUCUGAAUGUC AAGAA CAGG

[0782] 18524 ctrl_DGAT GUCAUGGGUGUCUGU 16840 UAACCCACAGACACCCA GGGUUA UGAC

[0783] 18525 ctrl_mTTR AACAGUGUUCUUGCUC 18528 UUAUAGAGCAAGAACAC UAUAA UGUU

[0784] 18526 ctrl_ANGPTL GCUCAACAUAUUUGAU 16811 UACUGAUCAAAUAUGUU 3 CAGUA GAGC

[0785] 18521 ctrl_DGAT- UGGGUUAUUUAAAAGA 18522 UUUCUUUUAAAUAACCC 1473 AA A

[0786] APOB_1 CCCUGAAGUUGAUGUG UAACACAUCAACUUCAG 12947 UUA 13247 GG

[0787] APOB_2 CUCUCAAACCCUAAGA UAAUCUUAGGGUUUGAG 12948 UUA 13248 AG

[0788] APOB_3 CCCUAAAGUAUGAGAA UAGUUCUCAUACUUUAG 12949 CUA 13249 GG

[0789] APOB_4 GCACUGGGGAUGAAGA UAAUCUUCAUCCCCAGU 12950 UUA 13250 GC

[0790] APOB_5 GGGAACUGUUGAAAGA AAAUCUUUCAACAGUUC 12951 UUU 13251 CC

[0791] APOB_6 GACAAGAGCUUAUGGG AAUCCCAUAAGCUCUUG 12952 AUU 13252 UC

[0792] APOB_7 GAUCAAAGUUAAUUGG UUCCCAAUUAACUUUGA 12953 GAA 13253 UC

[0793] APOB_8 CGAGAGACCCUAGAAG UAUCUUCUAGGGUCUCU 12954 AUA 13254 CG

[0794] APOB_9 GGAAAAGGGUCAUGGA AUUUCCAUGACCCUUUU 12955 AAU 13255 CC

[0795] APOB_10 CGGGAAUAUUCAGGAA UAGUUCCUGAAUAUUCC 12956 CUA 13256 CG

[0796] APOB_11 CCCAUGGUCUUGAGUU UUUAACUCAAGACCAUG 12957 AAA 13257 GG

[0797] APOB_12 CGUGGGUUCCAAAUUA UAUUAAUUUGGAACCCA 12958 AUA 13258 CG

[0798] APOB_13 GUACUGGGUUAAUGG UUGACCAUUAACCCAGU 12959 UCAA 13259 AC

[0799] APOB_14 CCCUGGACAUUCAGAA UUGUUCUGAAUGUCCAG 12960 CAA 13260 GG

[0800] APOB_15 CAAUGAAGGGAAUUUG UUUCAAAUUCCCUUCAU 12961 AAA 13261 UG

[0801] APOB_16 GGAAGGGCUCAAAGAA UCAUUCUUUGAGCCCUU 12962 UGA 13262 CC

[0802] APOB_17 GAAAUGCUAUUGAGGG UUUCCCUCAAUAGCAUU 12963 AAA 13263 UC

[0803] APOB_18 GGGAGGAGGAACAAAU UUUAUUUGUUCCUCCUC 12964 AAA 13264 CC

[0804] APOB_19 GUAUAGGGAACUGUUG UUUCAACAGUUCCCUAU 12965 AAA 13265 AC

[0805]

[0806] 12966 APOB_20 CACGUGGGUUCCAAAU 13266 UUAAUUUGGAACCCACG UAA UG

[0807] APOB_21 GCACGUGGGUUCCAAA UAAUUUGGAACCCACGU 12967 UUA 13267 GC

[0808] APOB_22 GUCCCAGGUAUAUUCG UUUCGAAUAUACCUGGG 12968 AAA 13268 AC

[0809] APOB_23 GUUCCAUGUCCCAUUU UGUAAAUGGGACAUGGA 12969 ACA 13269 AC

[0810] APOB_24 GUACUGUCCCAGGUAU AAUAUACCUGGGACAGU 12970 AUU 13270 AC

[0811] APOB_25 CCAAUUUCCCUGUGGA AGAUCCACAGGGAAAUU 12971 UCU 13271 GG

[0812] APOB_26 CCAUGGGCAAUAUUAC UAGGUAAUAUUGCCCAU 12972 CUA 13272 GG

[0813] APOB_27 GGGUCCUUUAUGAUUA ACAUAAUCAUAAAGGAC 12973 UGU 13273 CC

[0814] APOB_28 GUUCAGGGUGUGGAG UAAACUCCACACCCUGA 12974 UUUA 13274 AC

[0815] APOB_29 CCCUGAAUGCUAACAC UUAGUGUUAGCAUUCAG 12975 UAA 13275 GG

[0816] APOB_30 CGGGAAUCUGAUGAG UUUCCUCAUCAGAUUCC 12976 GAAA 13276 CG

[0817] APOB_31 CCCUAUUCUCUGGUAA UAGU UACCAGAGAAUAG 12977 CUA 13277 GG

[0818] APOB_32 CAGGAAGGGCUCAAAG AUUCUUUGAGCCCUUCC 12978 AAU 13278 UG

[0819] APOB_33 CAAACAAUGAAGGGAA AAAUUCCCUUCAUUGUU 12979 UUU 13279 UG

[0820] APOB_34 GCCCUGAAUGCUAACA UAGUGUUAGCAUUCAGG 12980 CUA 13280 GC

[0821] APOB_35 GGUAAAAUUCCCUGAA AACUUCAGGGAAUUUUA 12981 GUU 13281 CC

[0822] APOB_36 CCAUGAUUUCCCUGAC AAGGUCAGGGAAAUCAU 12982 CUU 13282 GG

[0823] APOB_37 GGAAAUGCUAUUGAGG UUCCCUCAAUAGCAUUU 12983 GAA 13283 CC

[0824] APOB_38 CACAAACAAUGAAGGG AUUCCCUUCAUUGUUUG 12984 AAU 13284 UG

[0825] APOB_39 GGAUAUACACUAGGGA UCCUCCCUAGUGUAUAU 12985 GGA 13285 CC

[0826] APOB_40 CAAGGGUGUUAUUUCC UAUGGAAAUAACACCCU 12986 AUA 13286 UG

[0827] APOB_41 CCCUAGAAAUCUCAAG AAGCUUGAGAUUUCUAG 12987 CUU 13287 GG

[0828] APOB_42 CAUUCAAUUGGGAGAG UGUCUCUCCCAAUUGAA 12988 ACA 13288 UG

[0829] APOB_43 GGGAACACAUGAAUCA UUGUGAUUCAUGUGUUC 12989 CAA 13289 CC

[0830] APOB_44 GUCAAGGGUUCGGUU AAAGAACCGAACCCUUG 12990 CUUU 13290 AC

[0831] APOB_45 CUCAAACCCUAAGAUU AUUAAUCUUAGGGUUUG 12991 AAU 13291 AG

[0832] APOB_46 CACUAAAUUCCCAUGG AGACCAUGGGAAUUUAG 12992 UCU 13292 UG

[0833] APOB_47 GAAACAACCCAGUCUC UUUGAGACUGGGUUGU 12993 AAA 13293 UUC

[0834] APOB_48 GCCCUAUUCUCUGGUA AGUUACCAGAGAAUAGG 12994 ACU 13294 GC

[0835] APOB_49 GUGACAAAUAUGGGCA UGAUGCCCAUAUUUGUC

[0836]

[0837] 12995 UCA 13295 AC APOB_50 GGAUUCAUUCUGGGU AAAGACCCAGAAUGAAU 12996 CUUU 13296 CC

[0838] APOB_51 GGAGGGUAGUCAUAAC ACUGUUAUGACUACCCU 12997 AGU 13297 CC

[0839] APOB_52 CAAUGGGAAACUACGG UAGCCGUAGUUUCCCAU 12998 CUA 13298 UG

[0840] APOB_53 CUCAAGACCCAAUUUA UGUUAAAUUGGGUCUUG 12999 ACA 13299 AG

[0841] APOB_54 CAUUGGUAGAGCAAGG AACCCUUGCUCUACCAA 13000 GUU 13300 UG

[0842] APOB_55 GGGAUGAAGAUUACAC UAGGUGUAAUCUUCAUC 13001 CUA 13301 CC

[0843] APOB_56 GAGGGUAGUCAUAACA UACUGUUAUGACUACCC 13002 GUA 13302 UC

[0844] APOB_57 CCCUCAACUUUUCUAA AGUUUAGAAAAGUUGAG 13003 ACU 13303 GG

[0845] APOB_58 CAAAGUUAAUUGGGAA UUCUUCCCAAUUAACUU 13004 GAA 13304 UG

[0846] APOB_59 GGGUUCCAAAUUAAUA AACUAUUAAUUUGGAAC 13005 GUU 13305 CC

[0847] APOB_60 CCCUCAAACAGACAUG AGUCAUGUCUGUUUGAG 13006 ACU 13306 GG

[0848] APOB_61 GGGAACUACAAUUUCA AAAUGAAAUUGUAGUUC 13007 UUU 13307 CC

[0849] APOB_62 GG U U AACAGGGAAGAU UCUAUCUUCCCUGUUAA 13008 AGA 13308 CC

[0850] APOB_63 GAAGGGAAGGCAGAGU UAAACUCUGCCUUCCCU 13009 UUA 13309 UC

[0851] APOB_64 CCCACUUGCUCUCAUC UUUGAUGAGAGCAAGUG 13010 AAA 13310 GG

[0852] APOB_65 GGGAGGAACUUUGCAC AUAGUGCAAAGUUCCUC 13011 UAU 13311 CC

[0853] APOB_66 GAGAUUCCCUCCAUUA ACUUAAUGGAGGGAAUC 13012 AGU 13312 UC

[0854] APOB_67 CCCAGUCUCAAAAGGU UAAACCUUUUGAGACUG 13013 UUA 13313 GG

[0855] APOB_68 GAUAUACACUAGGGAG UUCCUCCCUAGUGUAUA 13014 GAA 13314 UC

[0856] APOB_69 GCAGGGCACUUCCAAA AAUUUUGGAAGUGCCCU 13015 AUU 13315 GC

[0857] APOB_70 CCCAAUUUAACAACAA UCAUUGUUGUUAAAUUG 13016 UGA 13316 GG

[0858] APOB_71 CUCCAUCCCUGUAAAA AACUUUUACAGGGAUGG 13017 GUU 13317 AG

[0859] APOB_72 CCCUUCUGAUAGAUGU ACCACAUCUAUCAGAAG 13018 GGU 13318 GG

[0860] APOB_73 GGGUAGUCAUAACAGU AGUACUGUUAUGACUAC 13019 ACU 13319 CC

[0861] APOB_74 GGUACUGUCCCAGGUA AUAUACCUGGGACAGUA 13020 UAU 13320 CC

[0862] APOB_75 CUUUGUGGCUUCCCAU AAUAUGGGAAGCCACAA 13021 AUU 13321 AG

[0863] APOB_76 GGGAGAGACAAGUUUC UGUGAAACUUGUCUCUC 13022 ACA 13322 CC

[0864] APOB_77 CGAUGUAUAGGGAACU AACAGUUCCCUAUACAU 13023 GUU 13323 CG

[0865] APOB_78 GACACCAAUGGGAAGU UAUACUUCCCAUUGGUG 13024 AUA 13324 UC

[0866]

[0867] 13025 APOB_79 GCCAUGGGCAAUAUUA 13325 AGGUAAUAUUGCCCAUG ecu GC

[0868] APOB_80 CCCUAACAGAUUUGAG AUCCUCAAAUCUGUUAG 13026 GAU 13326 GG

[0869] APOB_81 CUGACACCAAUGGGAA UACUUCCCAUUGGUGUC 13027 GUA 13327 AG

[0870] APOB_82 CCAUGUCCCAUUUACA AUCUGUAAAUGGGACAU 13028 GAU 13328 GG

[0871] APOB_83 GCAAAUGCUGACAUAG UCCCUAUGUCAGCAUUU 13029 GGA 13329 GC

[0872] APOB_84 CAGGGAACACAAUGCA UUUUGCAUUGUGUUCCC 13030 AAA 13330 UG

[0873] APOB_85 CUGGGUUAAUGGUCAA AACUUGACCAUUAACCC 13031 GUU 13331 AG

[0874] APOB_86 GGGCAGCUGUAUAGCA AUUUGCUAUACAGCUGC 13032 AAU 13332 CC

[0875] APOB_87 CAAUUGGGAGAGACAA AACUUGUCUCUCCCAAU 13033 GUU 13333 UG

[0876] APOB_88 GGGAAUAUUCAGGAAC AUAGUUCCUGAAUAUUC 13034 UAU 13334 CC

[0877] APOB_89 CAAGAUUGGGCUAAAC UACGUUUAGCCCAAUCU 13035 GUA 13335 UG

[0878] APOB_90 CCCCAGGACCUUUCAA AAUUUGAAAGGUCCUGG 13036 AUU 13336 GG

[0879] APOB_91 GACCCAAUUUAACAAC AUUGUUGUUAAAUUGGG 13037 AAU 13337 UC

[0880] APOB_92 CCCACAUCUCACACAC AUUGUGUGUGAGAUGU 13038 AAU 13338 GGG

[0881] APOB_93 CCCUGGAUAGCAACAC UUAGUGUUGCUAUCCAG 13039 UAA 13339 GG

[0882] APOB_94 CCAUUGAGAUUCCCUC AUGGAGGGAAUCUCAAU 13040 CAU 13340 GG

[0883] APOB_95 GCUGACAUAGGGAAUG UUCCAUUCCCUAUGUCA 13041 GAA 13341 GC

[0884] APOB_96 CGGAUUCAUUCUGGG AAGACCCAGAAUGAAUC 13042 UCUU 13342 CG

[0885] APOB_97 CAGCCCUAUUCUCUGG UUACCAGAGAAUAGGGC 13043 UAA 13343 UG

[0886] APOB_98 CACCAACAAUGGGAAA UAGUUUCCCAUUGUUGG 13044 CUA 13344 UG

[0887] APOB_99 GAUUGGGCUAAACGUA UCAUACGUUUAGCCCAA 13045 UGA 13345 UC

[0888] APOB_100 GGGCACUUCCAAAAUU AUCAAUUUUGGAAGUGC 13046 GAU 13346 CC

[0889] APOB_101 CCCUAGAAGAUACACG UCUCGUGUAUCUUCUAG 13047 AGA 13347 GG

[0890] APOB_102 CCCUUGUCAACUCUGA UGAUCAGAGUUGACAAG 13048 UCA 13348 GG

[0891] APOB_103 CUAUGUGUUCCCAAAA UGCUUUUGGGAACACAU 13049 GCA 13349 AG

[0892] APOB_104 CUGGAAACUCAAGACC UUGGGUCUUGAGUUUC 13050 CAA 13350 CAG

[0893] APOB_105 CUUCCCAACUCUCAAG UGACUUGAGAGUUGGG 13051 UCA 13351 AAG

[0894] APOB_106 CGCCGAGGCCCGCGC AGCAGCGCGGGCCUCG 13052 UGCU 13352 GCG

[0895] APOB_107 GGCCCGCGCUGCUGG AGCGCCAGCAGCGCGG 13053 CGCU 13353 GCC

[0896] APOB_108 CACCCUGAAAGAGGUG AUACACCUCUUUCAGGG

[0897]

[0898] 13054 UAU 13354 UG APOB_109 CCUUUACCCGGAGAAA AUCUUUCUCCGGGUAAA 13055 GAU 13355 GG

[0899] APOB_110 GUAUGGGAUGGUAGC UUGUGCUACCAUCCCAU 13056 ACAA 13356 AC

[0900] APOB_111 CAACCCCCUUCUGAUA AUCUAUCAGAAGGGGGU 13057 GAU 13357 UG

[0901] APOB_112 GGCUUCCCAUAUUGCC AUUGGCAAUAUGGGAAG 13058 AAU 13358 CC

[0902] APOB_113 GCUUCCCAUAUUGCCA UAUUGGCAAUAUGGGAA 13059 AUA 13359 GC

[0903] APOB_114 CUUCCCAUAUUGCCAA AUAUUGGCAAUAUGGGA 13060 UAU 13360 AG

[0904] APOB_115 CUUUUUGGGAAGCAAG AUCCUUGCUUCCCAAAA 13061 GAU 13361 AG

[0905] APOB_116 GAAGCAAGGAUUUUUC UGGGAAAAAUCCUUGCU 13062 CCA 13362 UC

[0906] APOB_117 CAAGGAUUUUUCCCAG UGUCUGGGAAAAAUCCU 13063 ACA 13363 UG

[0907] APOB_118 GAU U U U UCCCAGACAG ACACUGUCUGGGAAAAA 13064 UGU 13364 UC

[0908] APOB_119 CCCAGACAGUGUCAAC UUUGUUGACACUGUCUG 13065 AAA 13365 GG

[0909] APOB_120 CAAAGCUUUGUACUGG AACCCAGUACAAAGCUU 13066 GUU 13366 UG

[0910] APOB_121 CUAAAAGCUGGGAAGC UCAGCUUCCCAGCUUUU 13067 UGA 13367 AG

[0911] APOB_122 CCCUGAAGUUUGUAAC UGAGUUACAAACUUCAG 13068 UCA 13368 GG

[0912] APOB_123 CUUCCAAUUUCCCUGU UCCACAGGGAAAUUGGA 13069 GGA 13369 AG

[0913] APOB_124 CACAUCCCAGAAAACC AGAGGUUUUCUGGGAU 13070 UCU 13370 GUG

[0914] APOB_125 CCCAGAAAACCUCUUC UAAGAAGAGGUUUUCUG 13071 UUA 13371 GG

[0915] APOB_126 GAUGGCCGGGUCAAAU UAUAUUUGACCCGGCCA 13072 AUA 13372 UC

[0916] APOB_127 CGGGUCAAAUAUACCU UCAAGGUAUAUUUGACC 13073 UGA 13373 CG

[0917] APOB_128 GGGUCAAAUAUACCUU UUCAAGGUAUAUUUGAC 13074 GAA 13374 CC

[0918] APOB_129 GAGUUCCAAGUCCCUA AAGUAGGGACUUGGAAC 13075 CUU 13375 UC

[0919] APOB_130 GUUCCAAGUCCCUACU AAAAGUAGGGACUUGGA 13076 UUU 13376 AC

[0920] APOB_131 CAAGUCCCUACUUUUA UGGUAAAAGUAGGGACU 13077 CCA 13377 UG

[0921] APOB_132 GUCAAGAUUGAUGGGC ACUGCCCAUCAAUCUUG 13078 AGU 13378 AC

[0922] APOB_133 GAUAUGAAGAUGGAAC AGGGUUCCAUCUUCAUA 13079 ecu 13379 UC

[0923] APOB_134 CUAUCACUGGGAAGUG AAGCACUUCCCAGUGAU 13080 CUU 13380 AG

[0924] APOB_135 CACUGGGAAGUGCUUA UGAUAAGCACUUCCCAG 13081 UCA 13381 UG

[0925] APOB_136 CAUGAUGGGCUCAUAU AGCAUAUGAGCCCAUCA 13082 GCU 13382 UG

[0926] APOB_137 CAUACUGGGCAGCUGU UAUACAGCUGCCCAGUA 13083 AUA 13383 UG

[0927]

[0928] 13084 APOB_138 CUUUUACUCAGUGAGC 13384 UGGGCUCACUGAGUAAA CCA AG

[0929] APOB_139 GAGAAGCCCCAAGAAU UAAAUUCUUGGGGCUUC 13085 UUA 13385 UC

[0930] APOB_140 GCCCCAAGAAUUUACA AAUUGUAAAUUCUUGGG 13086 AUU 13386 GC

[0931] APOB_141 CCCAAGAAUUUACAAU ACAAUUGUAAAUUCUUG 13087 UGU 13387 GG

[0932] APOB_142 CACUCCAUUAACCUCC AUGGGAGGUUAAUGGA 13088 CAU 13388 GUG

[0933] APOB_143 CCAUUAACCUCCCAUU AAAAAUGGGAGGUUAAU 13089 UUU 13389 GG

[0934] APOB_144 CAUUAACCUCCCAUUU AAAAAAUGGGAGGUUAA 13090 UUU 13390 UG

[0935] APOB_145 CUCCCAUUUUUUGAGA AGGUCUCAAAAAAUGGG 13091 ecu 13391 AG

[0936] APOB_146 CAAUUGGGAACUACAA AAAUUGUAGUUCCCAAU 13092 UUU 13392 UG

[0937] APOB_147 CUAUCCAAGAUUGGGC UUAGCCCAAUCUUGGAU 13093 UAA 13393 AG

[0938] APOB_148 CCAAGAUUGGGCUAAA ACGUUUAGCCCAAUCUU 13094 CGU 13394 GG

[0939] APOB_149 GGGUUCACUGUUCCU UUUCAGGAACAGUGAAC 13095 GAAA 13395 CC

[0940] APOB_150 GUCCCCCUAACAGAUU UCAAAUCUGUUAGGGGG 13096 UGA 13396 AC

[0941] APOB_151 CAGAUAUAUAUCUCAG UCCCUGAGAUAUAUAUC 13097 GGA 13397 UG

[0942] APOB_152 GCACAACUCUCAAACC UAGGGUUUGAGAGUUG 13098 CUA 13398 UGC

[0943] APOB_153 GCUAUUGAGGGAAAAU UUGAUUUUCCCUCAAUA 13099 CAA 13399 GC

[0944] APOB_154 CUAUUGAGGGAAAAUC UUUGAUUUUCCCUCAAU 13100 AAA 13400 AG

[0945] APOB_155 CAGAUUCUCAGAUGAG UCCCUCAUCUGAGAAUC 13101 GGA 13401 UG

[0946] APOB_156 CUCAGAUGAGGGAACA AUGUGUUCCCUCAUCUG 13102 CAU 13402 AG

[0947] APOB_157 CCACAAACAAUGAAGG UUCCCUUCAUUGUUUGU 13103 GAA 13403 GG

[0948] APOB_158 CCAUUAAGGUUAACAG UCCCUGUUAACCUUAAU 13104 GGA 13404 GG

[0949] APOB_159 CAU U AAGG U U AACAGG UUCCCUGUUAACCUUAA 13105 GAA 13405 UG

[0950] APOB_160 CAGGGAAGAUAGACUU AGGAAGUCUAUCUUCCC 13106 ecu 13406 UG

[0951] APOB_161 GGGAAGAUAGACUUCC UCAGGAAGUCUAUCUUC 13107 UGA 13407 CC

[0952] APOB_162 GAACAUUAUGGAGGCC AUGGGCCUCCAUAAUGU 13108 CAU 13408 UC

[0953] APOB_163 CAUUAUGGAGGCCCAU UACAUGGGCCUCCAUAA 13109 GUA 13409 UG

[0954] APOB_164 GAUUUCUCUCUAUGGG UUUCCCAUAGAGAGAAA 13110 AAA 13410 UC

[0955] APOB_165 CUCUCUAUGGGAAAAA UGUUUUUUCCCAUAGAG 13111 ACA 13411 AG

[0956] APOB_166 CUAUGGGAAAAAACAG AGCCUGUUUUUUCCCAU 13112 GCU 13412 AG

[0957] APOB_167 GGGAAAAAACAGGCUU UUCAAGCCUGUUUUUUC

[0958]

[0959] 13113 GAA 13413 CC APOB_168 CCUGCCAUGGGCAAUA UAAUAUUGCCCAUGGCA 13114 UUA 13414 GG

[0960] APOB_169 CAAGAAAAAGGGGAUU UUCAAUCCCCUUUUUCU 13115 GAA 13415 UG

[0961] APOB_170 GAAAAAGGGGAUUGAA AACUUCAAUCCCCUUUU 13116 GUU 13416 UC

[0962] APOB_171 CAACAAAUUUGUGGAG ACCCUCCACAAAUUUGU 13117 GGU 13417 UG

[0963] APOB_172 CAACAACCACAAAAGC UGGGCUUUUGUGGUUG 13118 CCA 13418 UUG

[0964] APOB_173 GCCCAAAUUCCAAUUU UCAAAAUUGGAAUUUGG 13119 UGA 13419 GC

[0965] APOB_174 GCAUAUAUUCCCUCUG UCCCAGAGGGAAUAUAU 13120 GGA 13420 GC

[0966] APOB_175 CUAGAGGGCCUCUUUU UGAAAAAGAGGCCCUCU 13121 UCA 13421 AG

[0967] APOB_176 CAUUCUGGGUCUUUCC UCUGGAAAGACCCAGAA 13122 AGA 13422 UG

[0968] APOB_177 GUGUACACCAAAAACC UGGGGUUUUUGGUGUA 13123 CCA 13423 CAC

[0969] APOB_178 GUACACCAAAAACCCC AUUGGGGUUUUUGGUG 13124 AAU 13424 UAC

[0970] APOB_179 CCAAAAACCCCAAUGG UAGCCAUUGGGGUUUU 13125 CUA 13425 UGG

[0971] APOB_180 CAAAAACCCCAAUGGC AUAGCCAUUGGGGUUUU 13126 UAU 13426 UG

[0972] APOB_181 CCCAAUGGCUAUUCAU AGAAUGAAUAGCCAUUG 13127 UCU 13427 GG

[0973] APOB_182 CCAUCCCUGUAAAAGU AAAACUUUUACAGGGAU 13128 UUU 13428 GG

[0974] APOB_183 CCCUGUAAAAGUUUUG AGCCAAAACUUUUACAG 13129 GCU 13429 GG

[0975] APOB_184 CUCCUUGAUUCCCUUU AAAAAAGGGAAUCAAGG 13130 UUU 13430 AG

[0976] APOB_185 CCUUGAUUCCCUUUUU UCAAAAAAGGGAAUCAA 13131 UGA 13431 GG

[0977] APOB_186 GAUUCCCUUUUUUGAG UAUCUCAAAAAAGGGAA 13132 AUA 13432 UC

[0978] APOB_187 GUUUUGGGAACACACA UUUUGUGUGUUCCCAAA 13133 AAA 13433 AC

[0979] APOB_188 CUUCAGGAAUGGGAAG UUCCUUCCCAUUCCUGA 13134 GAA 13434 AG

[0980] APOB_189 GCACUAUGUUCAUAAG UCCCUUAUGAACAUAGU 13135 GGA 13435 GC

[0981] APOB_190 CUAUGUUCAUAAGGGA ACCUCCCUUAUGAACAU 13136 GGU 13436 AG

[0982] APOB_191 CAGUGAUUAUAUCCCA AUAUGGGAUAUAAUCAC 13137 UAU 13437 UG

[0983] APOB_192 GUGAUUAUAUCCCAUA ACAUAUGGGAUAUAAUC 13138 UGU 13438 AC

[0984] APOB_193 GAUUAUAUCCCAUAUG AAACAUAUGGGAUAUAA 13139 UUU 13439 UC

[0985] APOB_194 GGCCCUUCGUGAAGAA AUAUUCUUCACGAAGGG 13140 UAU 13440 CC

[0986] APOB_195 GCCCUUCGUGAAGAAU AAUAUUCUUCACGAAGG 13141 AUU 13441 GC

[0987] APOB_196 CCCUUCGUGAAGAAUA AAAUAUUCUUCACGAAG 13142 UUU 13442 GG

[0988]

[0989] 13143 APOB_197 GAUCCAGAUGGAAAAG 13443 UCCCUUUUCCAUCUGGA GGA UC

[0990] APOB_198 CAGUCAUGAACCCCUA AUGUAGGGGUUCAUGAC 13144 CAU 13444 UG

[0991] APOB_199 GUCAUGAACCCCUACA UCAUGUAGGGGUUCAU 13145 UGA 13445 GAC

[0992] APOB_200 GUAAAAGCUCAGUAUA UCUUAUACUGAGCUUUU 13146 AGA 13446 AC

[0993] APOB_201 CUGAAACUAAAUGAUC UUAGAUCAUUUAGUUUC 13147 UAA 13447 AG

[0994] APOB_202 CACAAAUUUCUAGAUU UCGAAUCUAGAAAUUUG 13148 CGA 13448 UG

[0995] APOB_203 GUGAUUGUCAAGAUAA UGUUUAUCUUGACAAUC 13149 ACA 13449 AC

[0996] APOB_204 GAGAAAUUGGUUGGAU UAAAUCCAACCAAUUUC 13150 UUA 13450 UC

[0997] APOB_205 GAACUGUUGAAAGAUU AUAAAUCUUUCAACAGU 13151 UAU 13451 UC

[0998] APOB_206 GAUAAACUUCAAAGAC UAAGUCUUUGAAGUUUA 13152 UUA 13452 UC

[0999] APOB_207 GUCAAGAAGCUUAAUG AUUCAUUAAGCUUCUUG 13153 AAU 13453 AC

[1000] APOB_208 CUUAAGCUCUCAAAUG UGUCAUUUGAGAGCUUA 13154 ACA 13454 AG

[1001] APOB_209 GGAAUAUUCAGGAACU AAUAGUUCCUGAAUAUU 13155 AUU 13455 CC

[1002] APOB_210 CUUAUCAGCAAGCUAU UUUAUAGCUUGCUGAUA 13156 AAA 13456 AG

[1003] APOB_211 CUCUGAUUACUAUGAA UUUUUCAUAGUAAUCAG 13157 AAA 13457 AG

[1004] APOB_212 CUUGACAUGUUGAUAA UCUUUAUCAACAUGUCA 13158 AGA 13458 AG

[1005] APOB_213 GC U AU ACCAAAG AU GA UUAUCAUCUUUGGUAUA 13159 UAA 13459 GC

[1006] APOB_214 GUCCUUUAUGAUUAUG UGACAUAAUCAUAAAGG 13160 UCA 13460 AC

[1007] APOB_215 GCAAUGUGGCAACAGA AUUUCUGUUGCCACAUU 13161 AAU 13461 GC

[1008] APOB_216 GCCUAUAUUGAUAAAA UGGUUUUAUCAAUAUAG 13162 CCA 13462 GC

[1009] APOB_217 GAUUGUCAAGAUAAAC AUUGUUUAUCUUGACAA 13163 AAU 13463 UC

[1010] APOB_218 GAACACAUGAAUCACA AUUUGUGAUUCAUGUGU 13164 AAU 13464 UC

[1011] APOB_219 GAAAUGUGUCCAAAGU UGUACUUUGGACACAUU 13165 ACA 13465 UC

[1012] APOB_220 GAUAGCAACACUAAAU AGUAUUUAGUGUUGCUA 13166 ACU 13466 UC

[1013] APOB_221 CAAAAUCAACUUUAAU UUCAUUAAAGUUGAUUU 13167 GAA 13467 UG

[1014] APOB_222 CAUGGAAUUUAAGUAU AUCAUACUUAAAUUCCA 13168 GAU 13468 UG

[1015] APOB_223 C AAAG AAG U C AAG AU U AUCAAUCUUGACUUCUU 13169 GAU 13469 UG

[1016] APOB_224 CUCAAACAGACAUGAC AAAGUCAUGUCUGUUUG 13170 UUU 13470 AG

[1017] APOB_225 GGAUUACAGUUGCAAA AUAUUUGCAACUGUAAU 13171 UAU 13471 CC

[1018] APOB_226 CUCAAAAGGUUUACUA UAUUAGUAAACCUUUUG

[1019]

[1020] 13172 AUA 13472 AG APOB_227 GAAACAAUGCAUUAGA AAAUCUAAUGCAUUGUU 13173 UUU 13473 UC

[1021] APOB_228 GAUAACAGGAAGAUAU UUCAUAUCUUCCUGUUA 13174 GAA 13474 UC

[1022] APOB_229 GAGUGAUUGUCAAGAU UUUAUCUUGACAAUCAC 13175 AAA 13475 UC

[1023] APOB_230 CAAU U U AACAACAAUG AUUCAUUGUUGUUAAAU 13176 AAU 13476 UG

[1024] APOB_231 GAAGCAUUAAAACUGU AAAACAGUUUUAAUGCU 13177 UUU 13477 UC

[1025] APOB_232 C AG AG U U AAU GAU GAA AGAUUCAUCAUUAACUC 13178 UCU 13478 UG

[1026] APOB_233 CCUUAUCAGCAAGCUA UUAUAGCUUGCUGAUAA 13179 UAA 13479 GG

[1027] APOB_234 GACUCAAUGGUGAAAU UGAAUUUCACCAUUGAG 13180 UCA 13480 UC

[1028] APOB_235 GAAGUUGAUGUGUUAA UUGUUAACACAUCAACU 13181 CAA 13481 UC

[1029] APOB_236 GCCUUAUCAGCAAGCU UAUAGCUUGCUGAUAAG 13182 AUA 13482 GC

[1030] APOB_237 CAACAACUAUCAUAAG UGUCUUAUGAUAGUUGU 13183 ACA 13483 UG

[1031] APOB_238 GGCAAUAUUACCUAUG AAUCAUAGGUAAUAUUG 13184 AUU 13484 CC

[1032] APOB_239 CUAUAUUGAUAAAACC UAUGGUUUUAUCAAUAU 13185 AUA 13485 AG

[1033] APOB_240 CCUAUAUUGAUAAAAC AUGGUUUUAUCAAUAUA 13186 CAU 13486 GG

[1034] APOB_241 CACCAAAUCCUAUAAU UUCAUUAUAGGAUUUGG 13187 GAA 13487 UG

[1035] APOB_242 CAUCAGUUCAGAUAAA AAGUUUAUCUGAACUGA 13188 CUU 13488 UG

[1036] APOB_243 GAUAACCGUGCCUGAA AGAUUCAGGCACGGUUA 13189 UCU 13489 UC

[1037] APOB_244 CUACAACAAGUUAAGA UUAUCUUAACUUGUUGU 13190 UAA 13490 AG

[1038] APOB_245 CAUGAAUCACAAAUUA AACUAAUUUGUGAUUCA 13191 GUU 13491 UG

[1039] APOB_246 CAAAUUUCUAGAUUCG AUUCGAAUCUAGAAAUU 13192 AAU 13492 UG

[1040] APOB_247 GCACAAACUAUAAUUC UCUGAAUUAUAGUUUGU 13193 AGA 13493 GC

[1041] APOB_248 GAUUUCAAGGAAUUGU UACACAAUUCCUUGAAA 13194 GUA 13494 UC

[1042] APOB_249 GAACAAUCCUCAGAGU UUAACUCUGAGGAUUGU 13195 UAA 13495 UC

[1043] APOB_250 CCUACAACAAGUUAAG UAUCUUAACUUGUUGUA 13196 AUA 13496 GG

[1044] APOB_251 CACAAACAGUCUGAAC AAUGUUCAGACUGUUUG 13197 AUU 13497 UG

[1045] APOB_252 GGAAAAUGGAGCCUAA UCUUUAGGCUCCAUUUU 13198 AGA 13498 CC

[1046] APOB_253 CCAUGUAGGAAUAAAU UCCAUUUAUUCCUACAU 13199 GGA 13499 GG

[1047] APOB_254 CUAUCAUAUCCGUGUA AUUUACACGGAUAUGAU 13200 AAU 13500 AG

[1048] APOB_255 CCAAAAUAACCUUAAU AUGAUUAAGGUUAUUUU 13201 CAU 13501 GG

[1049]

[1050] 13202 APOB_256 CUUACAACACUAAAGA 13502 UUAUCUUUAGUGUUGUA UAA AG

[1051] APOB_257 GAAUUUGAAAGUUCGU AAAACGAACUUUCAAAU 13203 UUU 13503 UC

[1052] APOB_258 CUUUCUCUCAUGAUUA UUGUAAUCAUGAGAGAA 13204 CAA 13504 AG

[1053] APOB_259 GUAGAUGAAACCAAUG UGUCAUUGGUUUCAUCU 13205 ACA 13505 AC

[1054] APOB_260 GUUAACAAAAUAUUCU UUGAGAAUAUUUUGUUA 13206 CAA 13506 AC

[1055] APOB_261 CAAGUUGAAGGAGACU AAUAGUCUCCUUCAACU 13207 AUU 13507 UG

[1056] APOB_262 CUACCUUACACAAUAA UGAUUAUUGUGUAAGGU 13208 UCA 13508 AG

[1057] APOB_263 GUACUCUACCGCUAAA UCCUUUAGCGGUAGAGU 13209 GGA 13509 AC

[1058] APOB_264 CACUCAUUGAUUUUCU UUCAGAAAAUCAAUGAG 13210 GAA 13510 UG

[1059] APOB_265 CCACAUUCCUUCCUUU UGUAAAGGAAGGAAUGU 13211 ACA 13511 GG

[1060] APOB_266 GUACCAUAAGCCAUAU AAAAUAUGGCUUAUGGU 13212 UUU 13512 AC

[1061] APOB_267 CAAAAGGUUUACUAAU AAUAUUAGUAAACCUUU 13213 AUU 13513 UG

[1062] APOB_268 GAACUACGAGCUGACU UAAAGUCAGCUCGUAGU 13214 UUA 13514 UC

[1063] APOB_269 GACAUGUUGAUAAAGA AUUUCUUUAUCAACAUG 13215 AAU 13515 UC

[1064] APOB_270 CUUCCUUUACAAUUGA AAGUCAAUUGUAAAGGA 13216 CUU 13516 AG

[1065] APOB_271 GAAAGAGAUGAAAUUU AGUAAAUUUCAUCUCUU 13217 ACU 13517 UC

[1066] APOB_272 CUCAAGAAUUCCAUAU UUCAUAUGGAAUUCUUG 13218 GAA 13518 AG

[1067] APOB_273 CUUACAUCCUGAACAU UUGAUGUUCAGGAUGUA 13219 CAA 13519 AG

[1068] APOB_274 GCAUCUUCGUGUUUCA AGUUGAAACACGAAGAU 13220 ACU 13520 GC

[1069] APOB_275 CCAAUAAGAUCAAUAG UUGCUAUUGAUCUUAUU 13221 CAA 13521 GG

[1070] APOB_276 CAUUCCAUCACAAAUC AAGGAUUUGUGAUGGAA 13222 CUU 13522 UG

[1071] APOB_277 CCAAAGUCCAUGAGUU AUUAACUCAUGGACUUU 13223 AAU 13523 GG

[1072] APOB_278 GAUCAAGAACCUGUUA AACUAACAGGUUCUUGA 13224 GUU 13524 UC

[1073] APOB_279 CAG AU AU U AAC AAAAU ACAAUUUUGUUAAUAUC 13225 UGU 13525 UG

[1074] APOB_280 GAUGUGUUAACAAAAU AAU AU U U UG U U AACACA 13226 AUU 13526 UC

[1075] APOB_281 GAUUCCUUUGCCUUUU ACCAAAAGGCAAAGGAA 13227 GGU 13527 UC

[1076] APOB_282 CAUUUGUUUAUUGAAA UAUUUUCAAUAAACAAA 13228 AUA 13528 UG

[1077] APOB_283 GUAUAUUAAAGAUAGU AUAACUAUCUUUAAUAU 13229 UAU 13529 AC

[1078] APOB_284 GGUUCAAUCAGUAUAA UACUUAUACUGAUUGAA 13230 GUA 13530 CC

[1079] APOB_285 GCAAUGUCCUACAACA ACUUGUUGUAGGACAUU

[1080]

[1081] 13231 AGU 13531 GC APOB_286 G AC AU AU AU GAU ACAA AAAUUGUAUCAUAUAUG 13232 UUU 13532 UC

[1082] APOB_287 CUAGAUUCGAAUAUCA AUUUGAUAUUCGAAUCU 13233 AAU 13533 AG

[1083] APOB_288 CUAUGUGUUCCCAAAA UGCUUUUGGGAACACAU 13049 GCA 13534 AG

[1084] APOB_289 CAACCUUAAUGAUUUU UUGAAAAUCAUUAAGGU 13235 CAA 13535 UG

[1085] APOB_290 GAUCAAUUUGUAAGAA AUUUUCUUACAAAUUGA 13236 AAU 13536 UC

[1086] APOB_291 GAUCAG U AU AU U AAAG UAUCUUUAAUAUACUGA 13237 AUA 13537 UC

[1087] APOB_292 G U U AUGAU U U AC AU GA AAAUCAUGUAAAUCAUA 13238 UUU 13538 AC

[1088] APOB_293 CCACUUUGGCUAUACC UUUGGUAUAGCCAAAGU 13239 AAA 13539 GG

[1089] APOB_294 CACAAGAUUGACAAGA UUUUCUUGUCAAUCUUG 13240 AAA 13540 UG

[1090] APOB_295 GAUGAAAUUUACUUAU AAGAUAAGUAAAUUUCA 13241 CUU 13541 UC

[1091] APOB_296 GAU AAAGAAAU U AAAG UGACUUUAAUUUCUUUA 13242 UCA 13542 UC

[1092] APOB_297 GAAU U U AAG U AU GAU U UGAAAUCAUACUUAAAU 13243 UCA 13543 UC

[1093] APOB_298 CAUAUAUGAUACAAUU UCAAAUUGUAUCAUAUA 13244 UGA 13544 UG

[1094] APOB_299 CAACUAAUAGAAGAUA UGUUAUCUUCUAUUAGU 13245 ACA 13545 UG

[1095] APOB_300 GGAAUCUUAUAUUUGA GGAUCAAAUAUAAGAUU

[1096]

[1097] 13246 UCC 13546 CC

[1098] Table 19

[1099] fA, fll, fC, fG = 2’-F ribonucleotides and mA, mil, mC, mG = 2’ OMe ribonucleotides. SEQ ID modified_sense modified antisense

[1100] ID NO

[1101] ctrl_ApoB mCmCmUmGmGmAfCfAfUmU mUfUmCfUmUfGmUfUmCfUmG mCmAmGmAmAmCmAmAmG fAmAfUmGfUmCfCmAfGmGmG 17826 18129 mAmA mU

[1102] ctrl_DGA mGmUmCmAmUmGfGfGfUmG mUfAmAfCmCfCmAfCmAfGmAf T mUmCmUmGmUmGmGmGmU CmAfCmCfCmAfUmGfAmCmU 17827 18130 mUmA mU

[1103] ctrl_mTT mAmAmCmAmGmUfGfUfUmC mUfUmAfUmAfGmAfGmCfAmAf R mUmUmGmCmUmCmUmAmU GmAfAmCfAmCfUmGfUmUmU 17828 18131 mAmA mU

[1104] ctrl_ANG mGmCmUmCmAmAfCfAfUmA mUfAmCfUmGfAmUfCmAfAmAf PTL3 mUmUmUmGmAmUmCmAmG UmAfUmGfUmUfGmAfGmCmU 17829 18132 mUmA mU

[1105] ctrl_DGAT mUmGmGmGmUmUfAfUfUmU mUfUmUfCmUfUmUfUmAfAmAf 17256 17541 -1473 mAmAmAmAmGmAmAmA UmAfAmCfCmCfAmCmA APOB_1 mCmCmCmUmGmAfAfGfUmU mUfAmAfCmAfCmAfUmCfAmAf 17830 18133 mGmAmUmGmUmGmUmUmA CmUfUmCfAmGfGmGmUmU APOB_2 mCmUmCmUmCmAfAfAfCmC mUfAmAfUmCfUmUfAmGfGmG 17831 18134 mCmUmAmAmGmAmUmUmA fUmUfUmGfAmGfAmGmUmU APOB_3 mCmCmCmUmAmAfAfGfUmA mUfAmGfUmUfCmUfCmAfUmAf 17832 18135 mUmGmAmGmAmAmCmUmA CmUfUmUfAmGfGmGmUmU APOB_4 mGmCmAmCmUmGfGfGfGmA mUfAmAfUmCfUmUfCmAfUmCf

[1106]

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[1108]

[1109] 17862 18164 AmGmGmGmAmAmUmUmU AmUfUmGfUmUfUmGmUmU APOB_34 mGmCmCmCmUmGfAfAfUmG mUfAmGfUmGfUmUfAmGfCmA 17863 18165 mCmUmAmAmCmAmCmUmA fUmUfCmAfGmGfGmCmUmU APOB_35 mGmGmUmAmAmAfAfUfUmC mAfAmCfUmUfCmAfGmGfGmA 17864 18166 mCmCmUmGmAmAmGmUmU fAmUfUmUfUmAfCmCmUmU APOB_36 mCmCmAmUmGmAfUfUfUmC mAfAmGfGmUfCmAfGmGfGmA 17865 18167 mCmCmUmGmAmCmCmUmU fAmAfUmCfAmUfGmGmUmU APOB_37 mGmGmAmAmAmUfGfCfUmA mUfUmCfCmCfUmCfAmAfUmAf 17866 18168 mUmUmGmAmGmGmGmAmA GmCfAmUfUmUfCmCmUmU APOB_38 mCmAmCmAmAmAfCfAfAmUm mAfUmUfCmCfCmUfUmCfAmUf 17867 18169 GmAmAmGmGmGmAmAmU UmGfUmUfUmGfUmGmUmU APOB_39 mGmGmAmUmAmUfAfCfAmC mUfCmCfUmCfCmCfUmAfGmU 17868 18170 mUmAmGmGmGmAmGmGmA fGmUfAmUfAmUfCmCmUmU APOB_40 mCmAmAmGmGmGfUfGfUmU mUfAmUfGmGfAmAfAmUfAmAf 17869 18171 mAmUmUmUmCmCmAmUmA CmAfCmCfCmUfUmGmUmU APOB_41 mCmCmCmUmAmGfAfAfAmU mAfAmGfCmUfUmGfAmGfAmU 17870 18172 mCmUmCmAmAmGmCmUmU fUmUfCmUfAmGfGmGmUmU APOB_42 mCmAmUmUmCmAfAfUfLImG mUfGmUfCmUfCmUfCmCfCmA 17871 18173 mGmGmAmGmAmGmAmCmA fAmUfUmGfAmAfUmGmUmU APOB_43 mGmGmGmAmAmCfAfCfAmU mUfUmGfUmGfAmUfUmCfAmU 17872 18174 mGmAmAmUmCmAmCmAmA fGmUfGmUfUmCfCmCmUmU APOB_44 mGmUmCmAmAmGfGfGfUmU mAfAmAfGmAfAmCfCmGfAmAf 17873 18175 mCmGmGmUmUmCmUmUmU CmCfCmUfUmGfAmCmUmU APOB_45 mCmUmCmAmAmAfCfCfCmU mAfUmUfAmAfUmCfUmUfAmGf 17874 18176 mAmAmGmAmUmUmAmAmU GmGfUmUfUmGfAmGmUmU APOB_46 mCmAmCmUmAmAfAfUfUmCm mAfGmAfCmCfAmUfGmGfGmA 17875 18177 CmCmAmUmGmGmUmCmU fAmUfUmUfAmGfUmGmUmU APOB_47 mGmAmAmAmCmAfAfCfCmCm mUfUmUfGmAfGmAfCmUfGmG 17876 18178 AmGmUmCmUmCmAmAmA fGmUfUmGfUmUfUmCmUmU APOB_48 mGmCmCmCmUmAfUfUfCmU mAfGmUfUmAfCmCfAmGfAmG 17877 18179 mCmUmGmGmUmAmAmCmU fAmAfUmAfGmGfGmCmUmU APOB_49 mGmUmGmAmCmAfAfAfUmA mUfGmAfUmGfCmCfCmAfUmA 17878 18180 mUmGmGmGmCmAmUmCmA fUmUfUmGfUmCfAmCmUmU APOB_50 mGmGmAmUmUmCfAfUfUmC m AfA m Af G mAfCmCfCmAfGmAf 17879 18181 mUmGmGmGmUmCmUmUmU AmUfGmAfAmUfCmCmUmU APOB_51 mGmGmAmGmGmGfUfAfGmU mAfCmUfGmUfUmAfUmGfAmC 17880 18182 mCmAmUmAmAmCmAmGmU fUmAfCmCfCmUfCmCmUmU APOB_52 mCmAmAmUmGmGfGfAfAmA mUfAmGfCmCfGmUfAmGfUmU 17881 18183 mCmUmAmCmGmGmCmUmA fUmCfCmCfAmUfUmGmUmU APOB_53 mCmUmCmAmAmGfAfCfCmC mUfGmUfUmAfAmAfUmUfGmG 17882 18184 mAmAmUmUmUmAmAmCmA fGmUfCmUfUmGfAmGmUmU APOB_54 mCmAmUmUmGmGfUfAfGmA mAfAmCfCmCfU mUfG mCfU mC 17883 18185 mGmCmAmAmGmGmGmUmU fUmAfCmCfAmAfUmGmUmU APOB_55 mGmGmGmAmUmGfAfAfGmA mUfAmGfGmUfGmUfAmAfUmC 17884 18186 mUmUmAmCmAmCmCmUmA fUmUfCmAfUmCfCmCmUmU APOB_56 mGmAmGmGmGmUfAfGfUmC mUfAmCfUmGfUmUfAmUfGmA 17885 18187 mAmUmAmAmCmAmGmUmA fCmUfAmCfCmCfUmCmUmU APOB_57 mCmCmCmUmCmAfAfCfUmU mAfGmUfUmUfAmGfAmAfAmAf 17886 18188 mUmUmCmUmAmAmAmCmU GmUfUmGfAmGfGmGmUmU APOB_58 mCmAmAmAmGmUfUfAfAmUm mUfUmCfUmUfCmCfCmAfAmUf 17887 18189 UmGmGmGmAmAmGmAmA UmAfAmCfUmUfUmGmUmU APOB_59 mGmGmGmUmUmCfCfAfAmA mAfAmCfUmAfUmUfAmAfUmUf 17888 18190 mUmUmAmAmUmAmGmUmU UmGfGmAfAmCfCmCmUmU APOB_60 mCmCmCmUmCmAfAfAfCmAm mAfGmUfCmAfUmGfUmCfUmG 17889 18191 GmAmCmAmUmGmAmCmU fUmUfUmGfAmGfGmGmUmU APOB_61 mGmGmGmAmAmCfUfAfCmA mAfAmAfUmGfAmAfAmUfUmGf 17890 18192 mAmUmUmUmCmAmUmUmU UmAfGmUfUmCfCmCmUmU APOB_62 mGmGmUmUmAmAfCfAfGmG mUfCmUfAmUfCmUfUmCfCmC 17891 18193 mGmAmAmGmAmUmAmGmA fUmGfUmUfAmAfCmCmUmU APOB_63 mGmAmAmGmGmGfAfAfGmG mUfAmAfAmCfUmCfUmGfCmCf

[1110]

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[1112]

[1113] 17921 18223 mAmCmAmCmAmCmAmAmU fGmAfUmGfUmGfGmGmUmU APOB_93 mCmCmCmUmGmGfAfUfAmG mUfUmAfGmUfGmUfUmGfCmU 17922 18224 mCmAmAmCmAmCmUmAmA fAmUfCmCfAmGfGmGmUmU APOB_94 mCmCmAmUmUmGfAfGfAmU mAfUmGfGmAfGmGfGmAfAmU 17923 18225 mUmCmCmCmUmCmCmAmU fCmUfCmAfAmUfGmGmUmU APOB_95 mGmCmUmGmAmCfAfUfAmG mUfUmCfCmAfUmUfCmCfCmU 17924 18226 mGmGmAmAmUmGmGmAmA fAmUfGmUfCmAfGmCmUmU APOB_96 mCmGmGmAmUmUfCfAfUmU mAfAmGfAmCfCmCfAmGfAmAf 17925 18227 mCmUmGmGmGmUmCmUmU UmGfAmAfUmCfCmGmUmU APOB_97 mCmAmGmCmCmCfUfAfUmU mUfUmAfCmCfAmGfAmGfAmAf 17926 18228 mCmUmCmUmGmGmUmAmA UmAfGmGfGmCfUmGmUmU APOB_98 mCmAmCmCmAmAfCfAfAmUm mUfAmGfUmUfUmCfCmCfAmU 17927 18229 GmGmGmAmAmAmCmUmA fUmGfUmUfGmGfUmGmUmU APOB_99 mGmAmUmUmGmGfGfCfUmA mUfCmAfUmAfCmGfUmUfUmAf 17928 18230 mAmAmCmGmUmAmUmGmA GmCfCmCfAmAfUmCmUmU APOB_10 mGmGmGmCmAmCfUfUfCmC mAfUmCfAmAfUmUfUmUfGmG 17929 18231 0 mAmAmAmAmUmUmGmAmU fAmAfGmUfGmCfCmCmUmU APOB_10 mCmCmCmUmAmGfAfAfGmA mUfCmUfCmGfUmGfUmAfUmC 17930 18232 1 mUmAmCmAmCmGmAmGmA fUmUfCmUfAmGfGmGmUmU APOB_10 mCmCmCmUmUmGfUfCfAmA mUfG mAfU mCfAmGfAmGfU mU 17931 18233 2 mCmUmCmUmGmAmUmCmA fGmAfCmAfAmGfGmGmUmU APOB_10 mCmUmAmUmGmUfGfUfUmC mUfGmCfUmUfUmUfGmGfGmA 17932 18234 3 mCmCmAmAmAmAmGmCmA fAmCfAmCfAmUfAmGmUmU APOB_10 mCmUmGmGmAmAfAfCfUmC mUfUmGfGmGfUmCfUmUfGmA 17933 18235 4 mAmAmGmAmCmCmCmAmA fGmUfUmUfCmCfAmGmUmU APOB_10 mCmUmUmCmCmCfAfAfCmU mUfGmAfCmUfUmGfAmGfAmG 17934 18236 5 mCmUmCmAmAmGmUmCmA fUmUfGmGfGmAfAmGmUmU APOB_10 mCmGmCmCmGmAfGfGfCmC mAfGmCfAmGfCmGfCmGfGm 17935 18237 6 mCmGmCmGmCmUmGmCmU GfCmCfUmCfGmGfCmGmUmU APOB_10 mGmGmCmCmCmGfCfGfCmU mAfGmCfGmCfCmAfGmCfAmG 17936 18238 7 mGmCmUmGmGmCmGmCmU fCmGfCmGfGmGfCmCmUmU APOB_10 mCmAmCmCmCmUfGfAfAmA mAfU mAfC mAfCmCfU mCfU mUf 17937 18239 8 mGmAmGmGmUmGmUmAmU UmCfAmGfGmGfUmGmUmU APOB_10 mCmCmUmUmUmAfCfCfCmG mAfUmCfUmUfUmCfUmCfCmG 17938 18240 9 mGmAmGmAmAmAmGmAmU fGmGfUmAfAmAfGmGmUmU APOB_11 mGmUmAmUmGmGfGfAfUmG mUfUmGfUmGfCmUfAmCfCmA 17939 18241 0 mGmUmAmGmCmAmCmAmA fUmCfCmCfAmUfAmCmUmU APOB_11 mCmAmAmCmCmCfCfCfUmU mAfU mCfU mAfU mCfAmGfAmAf 17940 18242 1 mCmUmGmAmUmAmGmAmU GmGfGmGfGmUfUmGmUmU APOB_11 mGmGmCmUmUmCfCfCfAmU mAfUmUfGmGfCmAfAmUfAmUf 17941 18243 2 mAmUmUmGmCmCmAmAmU GmGfGmAfAmGfCmCmUmU APOB_11 mGmCmUmUmCmCfCfAfUmA mUfAmUfUmGfGmCfAmAfUmAf 17942 18244 3 mUmUmGmCmCmAmAmUmA UmGfGmGfAmAfGmCmUmU APOB_11 mCmUmUmCmCmCfAfUfAmU mAfUmAfUmUfGmGfCmAfAmUf 17943 18245 4 mUmGmCmCmAmAmUmAmU AmUfGmGfGmAfAmGmUmU APOB_11 mCmUmUmUmUmUfGfGfGmA mAfUmCfCmUfUmGfCmUfUmC 17944 18246 5 mAmGmCmAmAmGmGmAmU fCmCfAmAfAmAfAmGmUmU APOB_11 mGmAmAmGmCmAfAfGfGmA mUfGmGfGmAfAmAfAmAfUmCf 17945 18247 6 mUmUmUmUmUmCmCmCmA CmUfUmGfCmUfUmCmUmU APOB_11 mCmAmAmGmGmAfUfUfUmU mUfGmUfCmUfGmGfGmAfAmA 17946 18248 7 mUmCmCmCmAmGmAmCmA fAmAfUmCfCmUfUmGmUmU APOB_11 mGmAmUmUmUmUfUfCfCmC mAfCmAfCmUfGmUfCmUfGmG 17947 18249 8 mAmGmAmCmAmGmUmGmU fGmAfAmAfAmAfUmCmUmU APOB_11 mCmCmCmAmGmAfCfAfGmU mUfUmUfGmUfUmGfAmCfAmC 17948 18250 9 mGmUmCmAmAmCmAmAmA fUmGfUmCfUmGfGmGmUmU APOB_12 mCmAmAmAmGmCfUfUfLImG mAfAmCfCmCfAmGfUmAfCmAf 17949 18251 0 mUmAmCmUmGmGmGmUmU AmAfGmCfUmUfUmGmUmU APOB_12 mCmUmAmAmAmAfGfCfUmG mUfCmAfGmCfUmUfCmCfCmA 17950 18252 1 mGmGmAmAmGmCmUmGmA fGmCfUmUfUmUfAmGmUmU APOB_12 mCmCmCmUmGmAfAfGfUmU mUfGmAfGmUfUmAfCmAfAmAf

[1114]

[1115] 17951 18253 2 mUmGmUmAmAmCmUmCmA CmUfUmCfAmGfGmGmUmU APOB_12 mCmUmUmCmCmAfAfUfUmU mUfCmCfAmCfAmGfGmGfAmA 17952 18254 3 mCmCmCmUmGmUmGmGmA fAmUfUmGfGmAfAmGmUmU APOB_12 mCmAmCmAmUmCfCfCfAmG mAfGmAfGmGfUmUfUmUfCmU 17953 18255 4 mAmAmAmAmCmCmUmCmU fGmGfGmAfUmGfUmGmUmU APOB_12 mCmCmCmAmGmAfAfAfAmCm mUfAmAfGmAfAmGfAmGfGmU 17954 18256 5 CmUmCmUmUmCmUmUmA fUmUfUmCfUmGfGmGmUmU APOB_12 mGmAmUmGmGmCfCfGfGmG mUfAmUfAmUfUmUfGmAfCmCf 17955 18257 6 mUmCmAmAmAmUmAmUmA CmGfGmCfCmAfUmCmUmU APOB_12 mCmGmGmGmUmCfAfAfAmU mUfCmAfAmGfGmUfAmUfAmUf 17956 18258 7 mAmUmAmCmCmUmUmGmA UmUfGmAfCmCfCmGmUmU APOB_12 mGmGmGmUmCmAfAfAfUmA mUfUmCfAmAfGmGfUmAfUmAf 17957 18259 8 mUmAmCmCmUmUmGmAmA UmUfUmGfAmCfCmCmUmU APOB_12 mGmAmGmUmUmCfCfAfAmG mAfAmGfUmAfGmGfGmAfCmU 17958 18260 9 mUmCmCmCmUmAmCmUmU fUmGfGmAfAmCfUmCmUmU APOB_13 mGmUmUmCmCmAfAfGfUmC mAfAmAfAmGfUmAfGmGfGmAf 17959 18261 0 mCmCmUmAmCmUmUmUmU CmUfUmGfGmAfAmCmUmU 18262 APOB_13 mCmAmAmGmUmCfCfCfUmA mUfG mGfU mAfAmAfAmGfU mAf 17960 1 mCmUmUmUmUmAmCmCmA GmGfGmAfCmUfUmGmUmU 18263 APOB_13 mGmUmCmAmAmGfAfUfUmG mAfCmUfGmCfCmCfAmUfCmAf 17961 2 mAmUmGmGmGmCmAmGmU AmUfCmUfUmGfAmCmUmU 18264 APOB_13 mGmAmUmAmUmGfAfAfGmA mAfG mGfG mUfU mCfCmAfU mC 17962 3 mUmGmGmAmAmCmCmCmU fUmUfCmAfUmAfUmCmUmU 18265 APOB_13 mCmUmAmUmCmAfCfUfGmG mAfAmGfCmAfCmUfUmCfCmCf 17963 4 mGmAmAmGmUmGmCmUmU AmGfUmGfAmUfAmGmUmU 18266 APOB_13 mCmAmCmUmGmGfGfAfAmG mUfGmAfUmAfAmGfCmAfCmUf 17964 5 mUmGmCmUmUmAmUmCmA UmCfCmCfAmGfUmGmUmU 18267 APOB_13 mCmAmUmGmAmUfGfGfGmC mAfGmCfAmUfAmUfGmAfGmC 17965 6 mUmCmAmUmAmUmGmCmU fCmCfAmUfCmAfUmGmUmU 18268 APOB_13 mCmAmUmAmCmUfGfGfGmC mUfAmUfAmCfAmGfCmUfGmC 17966 7 mAmGmCmUmGmUmAmUmA fCmCfAmGfUmAfUmGmUmU 18269 APOB_13 mCmUmUmUmUmAfCfUfCmA mUfGmGfGmCfUmCfAmCfUmG 17967 8 mGmUmGmAmGmCmCmCmA fAmGfUmAfAmAfAmGmUmU 18270 APOB_13 mGmAmGmAmAmGfCfCfCmC mUfAmAfAmUfUmCfUmUfGmG 17968 9 mAmAmGmAmAmUmUmUmA fGmGfCmUfUmCfUmCmUmU 18271 APOB_14 mGmCmCmCmCmAfAfGfAmA mAfAmUfU mGfU mAfAmAfU mUf 17969 0 mUmUmUmAmCmAmAmUmU CmUfUmGfGmGfGmCmUmU 18272 APOB_14 mCmCmCmAmAmGfAfAfUmU mAfCmAfAmUfUmGfUmAfAmAf 17970 1 mUmAmCmAmAmUmUmGmU UmUfCmUfUmGfGmGmUmU 18273 APOB_14 mCmAmCmUmCmCfAfUfUmA mAfU mGfG mGfAmGfG mUfU mA 17971 2 mAmCmCmUmCmCmCmAmU fAmUfGmGfAmGfUmGmUmU 18274 APOB_14 mCmCmAmUmUmAfAfCfCmU mAfAmAfAmAfUmGfGmGfAmGf 17972 3 mCmCmCmAmUmUmUmUmU GmUfUmAfAmUfGmGmUmU 18275 APOB_14 mCmAmUmUmAmAfCfCfUmC mAfAmAfAmAfAmUfGmGfGmAf 17973 4 mCmCmAmUmUmUmUmUmU GmGfUmUfAmAfUmGmUmU 18276 APOB_14 mCmUmCmCmCmAfUfUfUmU mAfG mGfU mCfU mCfAmAfAmAf 17974 5 mUmUmGmAmGmAmCmCmU AmAfUmGfGmGfAmGmUmU 18277 APOB_14 mCmAmAmUmUmGfGfGfAmA mAfAmAfUmUfGmUfAmGfUmUf 17975 6 mCmUmAmCmAmAmUmUmU CmCfCmAfAmUfUmGmUmU 18278 APOB_14 mCmUmAmUmCmCfAfAfGmA mUfUmAfGmCfCmCfAmAfUmCf 17976 7 mUmUmGmGmGmCmUmAmA UmUfGmGfAmUfAmGmUmU 18279 APOB_14 mCmCmAmAmGmAfUfUfGmG mAfCmGfUmUfUmAfGmCfCmC 17977 8 mGmCmUmAmAmAmCmGmU fAmAfUmCfUmUfGmGmUmU 18280 APOB_14 mGmGmGmUmUmCfAfCfUmG mUfUmUfCmAfGmGfAmAfCmAf 17978 9 mUmUmCmCmUmGmAmAmA GmUfGmAfAmCfCmCmUmU 18281 APOB_15 mGmUmCmCmCmCfCfUfAmA mUfC mAfAmAfU mCfUmGfUmUf 17979 0 mCmAmGmAmUmUmUmGmA AmGfGmGfGmGfAmCmUmU 18282 APOB_15 mCmAmGmAmUmAfUfAfUmAm mUfCmCfCmUfGmAfGmAfUmA

[1116]

[1117] 17980 1 UmCmUmCmAmGmGmGmA fUmAfUmAfUmCfUmGmUmU 18283 APOB_15 mGmCmAmCmAmAfCfUfCmU mUfAmGfGmGfUmUfUmGfAmG 17981 2 mCmAmAmAmCmCmCmUmA fAmGfUmUfGmUfGmCmUmU 18284 APOB_15 mGmCmUmAmUmUfGfAfGmG mUfUmGfAmUfUmUfUmCfCmC 17982 3 mGmAmAmAmAmUmCmAmA fUmCfAmAfUmAfGmCmUmU 18285 APOB_15 mCmUmAmUmUmGfAfGfGmG mUfUmUfGmAfUmUfUmUfCmC 17983 4 mAmAmAmAmUmCmAmAmA fCmUfCmAfAmUfAmGmUmU 18286 APOB_15 mCmAmGmAmUmUfCfUfCmA mUfCmCfCmUfCmAfUmCfUmG 17984 5 mGmAmUmGmAmGmGmGmA fAmGfAmAfUmCfUmGmUmU 18287 APOB_15 mCmUmCmAmGmAfUfGfAmG mAfUmGfUmGfUmUfCmCfCmU 17985 6 mGmGmAmAmCmAmCmAmU fCmAfUmCfUmGfAmGmUmU 18288 APOB_15 mCmCmAmCmAmAfAfCfAmAm mUfUmCfCmCfUmUfCmAfUmU 17986 7 UmGmAmAmGmGmGmAmA fGmUfUmUfGmUfGmGmUmU 18289 APOB_15 mCmCmAmUmUmAfAfGfGmU mUfCmCfCmUfGmUfUmAfAmC 17987 8 mUmAmAmCmAmGmGmGmA fCmUfUmAfAmUfGmGmUmU 18290 APOB_15 mCmAmUmUmAmAfGfGfUmU mUfUmCfCmCfUmGfUmUfAmA 17988 9 mAmAmCmAmGmGmGmAmA fCmCfUmUfAmAfUmGmUmU 18291 APOB_16 mCmAmGmGmGmAfAfGfAmU mAfGmGfAmAfGmUfCmUfAmU 17989 0 mAmGmAmCmUmUmCmCmU fCmUfUmCfCmCfUmGmUmU 18292 APOB_16 mGmGmGmAmAmGfAfUfAmG mUfCmAfGmGfAmAfGmUfCmU 17990 1 mAmCmUmUmCmCmUmGmA fAmUfCmUfUmCfCmCmUmU 18293 APOB_16 mGmAmAmCmAmUfUfAfUmG mAfUmGfGmGfCmCfUmCfCmA 17991 2 mGmAmGmGmCmCmCmAmU fUmAfAmUfGmUfUmCmUmU 18294 APOB_16 mCmAmUmUmAmUfGfGfAmG mUfAmCfAmUfGmGfGmCfCmU 17992 3 mGmCmCmCmAmUmGmUmA fCmCfAmUfAmAfUmGmUmU 18295 APOB_16 mGmAmUmUmUmCfUfCfUmC mUfUmUfCmCfCmAfUmAfGmAf 17993 4 mUmAmUmGmGmGmAmAmA GmAfGmAfAmAfUmCmUmU 18296 APOB_16 mCmUmCmUmCmUfAfUfGmG mUfGmUfUmUfUmUfUmCfCmC 17994 5 mGmAmAmAmAmAmAmCmA fAmUfAmGfAmGfAmGmUmU 18297 APOB_16 mCmUmAmUmGmGfGfAfAmA mAfGmCfCmUfGmUfUmUfUmU 17995 6 mAmAmAmCmAmGmGmCmU fUmCfCmCfAmUfAmGmUmU 18298 APOB_16 mGmGmGmAmAmAfAfAfAmC mUfUmCfAmAfGmCfCmUfGmU 17996 7 mAmGmGmCmUmUmGmAmA fUmUfUmUfUmCfCmCmUmU 18299 APOB_16 mCmCmUmGmCmCfAfUfGmG mUfAmAfUmAfUmUfGmCfCmCf 17997 8 mGmCmAmAmUmAmUmUmA AmUfGmGfCmAfGmGmUmU 18300 APOB_16 mCmAmAmGmAmAfAfAfAmGm mUfUmCfAmAfUmCfCmCfCmUf 17998 9 GmGmGmAmUmUmGmAmA UmUfUmUfCmUfUmGmUmU 18301 APOB_17 mGmAmAmAmAmAfGfGfGmG mAfAmCfUmUfCmAfAmUfCmCf 17999 0 mAmUmUmGmAmAmGmUmU CmCfUmUfUmUfUmCmUmU 18302 APOB_17 mCmAmAmCmAmAfAfUfUmUm mAfCmCfCmUfCmCfAmCfAmAf 18000 1 GmUmGmGmAmGmGmGmU AmUfUmUfGmUfUmGmUmU 18303 APOB_17 mCmAmAmCmAmAfCfCfAmCm mUfGmGfGmCfUmUfUmUfGm 18001 2 AmAmAmAmGmCmCmCmA UfGmGfUmUfGmUfUmGmUmU 18304 APOB_17 mGmCmCmCmAmAfAfUfLImC mUfCmAfAmAfAmUfUmGfGmAf 18002 3 mCmAmAmUmUmUmUmGmA AmUfUmUfGmGfGmCmUmU 18305 APOB_17 mGmCmAmUmAmUfAfUfUmC mUfCmCfCmAfGmAfGmGfGmA 18003 4 mCmCmUmCmUmGmGmGmA fAmUfAmUfAmUfGmCmUmU 18306 APOB_17 mCmUmAmGmAmGfGfGfCmC mUfGmAfAmAfAmAfGmAfGmGf 18004 5 mUmCmUmUmUmUmUmCmA CmCfCmUfCmUfAmGmUmU 18307 APOB_17 mCmAmUmUmCmUfGfGfGmU mUfCmUfGmGfAmAfAmGfAmC 18005 6 mCmUmUmUmCmCmAmGmA fCmCfAmGfAmAfUmGmUmU 18308 APOB_17 mGmUmGmUmAmCfAfCfCmA mUfGmGfGmGfUmUfUmUfUm 18006 7 mAmAmAmAmCmCmCmCmA GfGmUfGmUfAmCfAmCmUmU 18309 APOB_17 mGmUmAmCmAmCfCfAfAmAm mAfUmUfGmGfGmGfUmUfUmU 18007 8 AmAmCmCmCmCmAmAmU fUmGfGmUfGmUfAmCmUmU 18310 APOB_17 mCmCmAmAmAmAfAfCfCmCm mUfAmGfCmCfAmUfUmGfGmG 18008 9 CmAmAmUmGmGmCmUmA fGmUfUmUfUmUfGmGmUmU 18311 APOB_18 mCmAmAmAmAmAfCfCfCmCm mAfUmAfGmCfCmAfUmUfGmG 18009 0 AmAmUmGmGmCmUmAmU fGmGfUmUfUmUfUmGmUmU 18312 APOB_18 mCmCmCmAmAmUfGfGfCmU mAfGmAfAmUfGmAfAmUfAmGf

[1118]

[1119] 18010 1 mAmUmUmCmAmUmUmCmU CmCfAmUfUmGfGmGmUmU 18313 APOB_18 mCmCmAmUmCmCfCfUfGmU mAfAmAfAmCfUmUfUmUfAmCf 18011 2 mAmAmAmAmGmUmUmUmU AmGfGmGfAmUfGmGmUmU 18314 APOB_18 mCmCmCmUmGmUfAfAfAmA mAfGmCfCmAfAmAfAmCfUmUf 18012 3 mGmUmUmUmUmGmGmCmU UmUfAmCfAmGfGmGmUmU 18315 APOB_18 mCmUmCmCmUmUfGfAfUmU mAfAmAfAmAfAmGfGmGfAmAf 18013 4 mCmCmCmUmUmUmUmUmU UmCfAmAfGmGfAmGmUmU 18316 APOB_18 mCmCmUmUmGmAfUfUfCmC mUfCmAfAmAfAmAfAmGfGmGf 18014 5 mCmUmUmUmUmUmUmGmA AmAfUmCfAmAfGmGmUmU 18317 APOB_18 mGmAmUmUmCmCfCfUfUmU mUfAmUfCmUfCmAfAmAfAmAf 18015 6 mUmUmUmGmAmGmAmUmA AmGfGmGfAmAfUmCmUmU 18318 APOB_18 mGmUmUmUmUmGfGfGfAmA mUfUmUfUmGfUmGfUmGfUmU 18016 7 mCmAmCmAmCmAmAmAmA fCmCfCmAfAmAfAmCmUmU 18319 APOB_18 mCmUmUmCmAmGfGfAfAmU mUfUmCfCmUfUmCfCmCfAmU 18017 8 mGmGmGmAmAmGmGmAmA fUmCfCmUfGmAfAmGmUmU 18320 APOB_18 mGmCmAmCmUmAfUfGfUmU mUfCmCfCmUfUmAfUmGfAmAf 18018 9 mCmAmUmAmAmGmGmGmA CmAfUmAfGmUfGmCmUmU 18321 APOB_19 mCmUmAmUmGmUfUfCfAmU mAfCmCfUmCfCmCfUmUfAmUf 18019 0 mAmAmGmGmGmAmGmGmU GmAfAmCfAmUfAmGmUmU 18322 APOB_19 mCmAmGmUmGmAfUfUfAmU mAfUmAfUmGfGmGfAmUfAmU 18020 1 mAmUmCmCmCmAmUmAmU fAmAfUmCfAmCfUmGmUmU 18323 APOB_19 mGmUmGmAmUmUfAfUfAmU mAfCmAfUmAfUmGfGmGfAmU 18021 2 mCmCmCmAmUmAmUmGmU fAmUfAmAfUmCfAmCmUmU 18324 APOB_19 mGmAmUmUmAmUfAfUfCmC mAfAmAfCmAfU mAfU mGfG mGf 18022 3 mCmAmUmAmUmGmUmUmU AmUfAmUfAmAfUmCmUmU 18325 APOB_19 mGmGmCmCmCmUfUfCfGmU mAfUmAfUmUfCmUfUmCfAmCf 18023 4 mGmAmAmGmAmAmUmAmU GmAfAmGfGmGfCmCmUmU 18326 APOB_19 mGmCmCmCmUmUfCfGfUmG mAfAmUfAmUfUmCfUmUfCmAf 18024 5 mAmAmGmAmAmUmAmUmU CmGfAmAfGmGfGmCmUmU 18327 APOB_19 mCmCmCmUmUmCfGfUfGmA mAfAmAfUmAfUmUfCmUfUmCf 18025 6 mAmGmAmAmUmAmUmUmU AmCfGmAfAmGfGmGmUmU 18328 APOB_19 mGmAmUmCmCmAfGfAfUmG mUfCmCfCmUfUmUfUmCfCmA 18026 7 mGmAmAmAmAmGmGmGmA fUmCfUmGfGmAfUmCmUmU 18329 APOB_19 mCmAmGmUmCmAfUfGfAmA mAfU mGfU mAfG mGfGmGfU mU 18027 8 mCmCmCmCmUmAmCmAmU fCmAfUmGfAmCfUmGmUmU 18330 APOB_19 mGmUmCmAmUmGfAfAfCmC mUfCmAfUmGfUmAfGmGfGmG 18028 9 mCmCmUmAmCmAmUmGmA fUmUfCmAfUmGfAmCmUmU 18331 APOB_20 mGmUmAmAmAmAfGfCfUmC mUfCmUfUmAfUmAfCmUfGmAf 18029 0 mAmGmUmAmUmAmAmGmA GmCfUmUfUmUfAmCmUmU 18332 APOB_20 mCmUmGmAmAmAfCfUfAmAm mUfUmAfGmAfUmCfAmUfUmUf 18030 1 AmUmGmAmUmCmUmAmA AmGfUmUfUmCfAmGmUmU 18333 APOB_20 mCmAmCmAmAmAfUfUfUmCm mUfC mGfAmAfU mCfU mAfGmAf 18031 2 UmAmGmAmUmUmCmGmA AmAfUmUfUmGfUmGmUmU 18334 APOB_20 mGmUmGmAmUmUfGfUfCmA mUfGmUfUmUfAmUfCmUfUmG 18032 3 mAmGmAmUmAmAmAmCmA fAmCfAmAfUmCfAmCmUmU 18335 APOB_20 mGmAmGmAmAmAfUfUfGmG mUfAmAfAmUfCmCfAmAfCmCf 18033 4 mUmUmGmGmAmUmUmUmA AmAfUmUfUmCfUmCmUmU 18336 APOB_20 mGmAmAmCmUmGfUfUfGmA mAfU mAfAmAfU mCfU mUfU mCf 18034 5 mAmAmGmAmUmUmUmAmU AmAfCmAfGmUfUmCmUmU 18337 APOB_20 mGmAmUmAmAmAfCfUfUmC mUfAmAfGmUfCmUfUmUfGmA 18035 6 mAmAmAmGmAmCmUmUmA fAmGfUmUfUmAfUmCmUmU 18338 APOB_20 mGmUmCmAmAmGfAfAfGmC mAfUmUfCmAfUmUfAmAfGmCf 18036 7 mUmUmAmAmUmGmAmAmU UmUfCmUfUmGfAmCmUmU 18339 APOB_20 mCmUmUmAmAmGfCfUfCmU mUfGmUfCmAfUmUfUmGfAmG 18037 8 mCmAmAmAmUmGmAmCmA fAmGfCmUfUmAfAmGmUmU 18340 APOB_20 mGmGmAmAmUmAfUfUfCmA mAfAmUfAmGfUmUfCmCfUmG 18038 9 mGmGmAmAmCmUmAmUmU fAmAfUmAfUmUfCmCmUmU 18341 APOB_21 mCmUmUmAmUmCfAfGfCmA mUfUmUfAmUfAmGfCmUfUmG

[1120]

[1121] 18039 0 mAmGmCmUmAmUmAmAmA fCmUfGmAfUmAfAmGmUmU 18342 APOB_21 mCmUmCmUmGmAfUfUfAmC mUfUmUfUmUfCmAfUmAfGmU 18040 1 mUmAmUmGmAmAmAmAmA fAmAfUmCfAmGfAmGmUmU 18343 APOB_21 mCmUmUmGmAmCfAfUfGmU mUfCmUfUmUfAmUfCmAfAmCf 18041 2 mUmGmAmUmAmAmAmGmA AmUfGmUfCmAfAmGmUmU 18344 APOB_21 mGmCmUmAmUmAfCfCfAmA mUfUmAfUmCfAmUfCmUfUmUf 18042 3 mAmGmAmUmGmAmUmAmA GmGfUmAfUmAfGmCmUmU 18345 APOB_21 mGmUmCmCmUmUfUfAfUmG mUfGmAfCmAfUmAfAmUfCmAf 18043 4 mAmUmUmAmUmGmUmCmA UmAfAmAfGmGfAmCmUmU 18346 APOB_21 mGmCmAmAmUmGfUfGfGmC mAfUmUfUmCfUmGfUmUfGmC 18044 5 mAmAmCmAmGmAmAmAmU fCmAfCmAfUmUfGmCmUmU 18347 APOB_21 mGmCmCmUmAmUfAfUfLImG mUfGmGfUmUfUmUfAmUfCmA 18045 6 mAmUmAmAmAmAmCmCmA fAmUfAmUfAmGfGmCmUmU 18348 APOB_21 mGmAmUmUmGmUfCfAfAmG mAfUmUfGmUfUmUfAmUfCmU 18046 7 mAmUmAmAmAmCmAmAmU fUmGfAmCfAmAfUmCmUmU 18349 APOB_21 mGmAmAmCmAmCfAfUfGmA mAfUmUfUmGfUmGfAmUfUmC 18047 8 mAmUmCmAmCmAmAmAmU fAmUfGmUfGmUfUmCmUmU 18350 APOB_21 mGmAmAmAmUmGfUfGfUmC mUfGmUfAmCfUmUfUmGfGmA 18048 9 mCmAmAmAmGmUmAmCmA fCmAfCmAfUmUfUmCmUmU 18351 APOB_22 mGmAmUmAmGmCfAfAfCmA mAfGmUfAmUfUmUfAmGfUmG 18049 0 mCmUmAmAmAmUmAmCmU fUmUfGmCfUmAfUmCmUmU 18352 APOB_22 mCmAmAmAmAmUfCfAfAmCm mUfUmCfAmUfUmAfAmAfGmUf 18050 1 UmUmUmAmAmUmGmAmA UmGfAmUfUmUfUmGmUmU 18353 APOB_22 mCmAmUmGmGmAfAfUfUmU mAfUmCfAmUfAmCfUmUfAmAf 18051 2 mAmAmGmUmAmUmGmAmU AmUfUmCfCmAfUmGmUmU 18354 APOB_22 mCmAmAmAmGmAfAfGfUmC mAfU mCfAmAfU mCfU mUfGmAf 18052 3 mAmAmGmAmUmUmGmAmU CmUfUmCfUmUfUmGmUmU 18355 APOB_22 mCmUmCmAmAmAfCfAfGmAm mAfAmAfGmUfCmAfUmGfUmCf 18053 4 CmAmUmGmAmCmUmUmU UmGfUmUfUmGfAmGmUmU 18356 APOB_22 mGmGmAmUmUmAfCfAfGmU mAfUmAfUmUfUmGfCmAfAmCf 18054 5 mUmGmCmAmAmAmUmAmU UmGfUmAfAmUfCmCmUmU 18357 APOB_22 mCmUmCmAmAmAfAfGfGmU mUfAmUfUmAfGmUfAmAfAmCf 18055 6 mUmUmAmCmUmAmAmUmA CmUfUmUfUmGfAmGmUmU 18358 APOB_22 mGmAmAmAmCmAfAfUfGmC mAfAmAfUmCfUmAfAmUfGmCf 18056 7 mAmUmUmAmGmAmUmUmU AmUfUmGfUmUfUmCmUmU 18359 APOB_22 mGmAmUmAmAmCfAfGfGmA mUfUmCfAmUfAmUfCmUfUmCf 18057 8 mAmG mAmU mAmU mG mAmA CmUfGmUfUmAfUmCmUmU 18360 APOB_22 mGmAmGmUmGmAfUfUfGmU mUfUmUfAmUfCmUfUmGfAmC 18058 9 mCmAmAmGmAmUmAmAmA fAmAfUmCfAmCfUmCmUmU 18361 APOB_23 mCmAmAmUmUmUfAfAfCmAm mAfUmUfCmAfUmUfGmUfUmG 18059 0 AmCmAmAmUmGmAmAmU fUmUfAmAfAmUfUmGmUmU 18362 APOB_23 mGmAmAmGmCmAfUfUfAmA mAfAmAfAmCfAmGfUmUfUmUf 18060 1 mAmAmCmUmGmUmUmUmU AmAfUmGfCmUfUmCmUmU 18363 APOB_23 mCmAmGmAmGmUfUfAfAmU mAfG mAfU mUfC mAfU mCfAmUf 18061 2 mGmAmUmGmAmAmUmCmU UmAfAmCfUmCfUmGmUmU 18364 APOB_23 mCmCmUmUmAmUfCfAfGmC mUfU mAfU mAfG mCfUmUfGmC 18062 3 mAmAmGmCmUmAmUmAmA fUmGfAmUfAmAfGmGmUmU 18365 APOB_23 mGmAmCmUmCmAfAfUfGmG mUfGmAfAmUfUmUfCmAfCmCf 18063 4 mUmGmAmAmAmUmUmCmA AmUfUmGfAmGfUmCmUmU 18366 APOB_23 mGmAmAmGmUmUfGfAfUmG mUfUmGfUmUfAmAfCmAfCmAf 18064 5 mUmGmUmUmAmAmCmAmA UmCfAmAfCmUfUmCmUmU 18367 APOB_23 mGmCmCmUmUmAfUfCfAmG mUfAmUfAmGfCmUfUmGfCmU 18065 6 mCmAmAmGmCmUmAmUmA fGmAfUmAfAmGfGmCmUmU 18368 APOB_23 mCmAmAmCmAmAfCfUfAmUm mUfGmUfCmUfUmAfUmGfAmU 18066 7 CmAmUmAmAmGmAmCmA fAmGfUmUfGmUfUmGmUmU 18369 APOB_23 mGmGmCmAmAmUfAfUfUmA mAfAmUfC mAfU mAfG mGfU mAf 18067 8 mCmCmUmAmUmGmAmUmU AmUfAmUfUmGfCmCmUmU 18370 APOB_23 mCmUmAmUmAmUfUfGfAmU mUfAmUfGmGfUmUfUmUfAmU 18068 9 mAmAmAmAmCmCmAmUmA fCmAfAmUfAmUfAmGmUmU 18371 APOB_24 mCmCmUmAmUmAfUfUfGmA mAfUmGfGmUfUmUfUmAfUmC

[1122]

[1123] 18069 0 mUmAmAmAmAmCmCmAmU fAmAfUmAfUmAfGmGmUmU 18372 APOB_24 mCmAmCmCmAmAfAfUfCmCm mUfU mCfAmUfUmAfU mAfGmG 18070 1 UmAmUmAmAmUmGmAmA fAmUfUmUfGmGfUmGmUmU 18373 APOB_24 mCmAmUmCmAmGfUfUfCmA mAfAmGfUmUfUmAfUmCfUmG 18071 2 mGmAmUmAmAmAmCmUmU fAmAfCmUfGmAfUmGmUmU 18374 APOB_24 mGmAmUmAmAmCfCfGfUmG mAfGmAfUmUfCmAfGmGfCmA 18072 3 mCmCmUmGmAmAmUmCmU fCmGfGmUfUmAfUmCmUmU 18375 APOB_24 mCmUmAmCmAmAfCfAfAmGm mUfUmAfUmCfUmUfAmAfCmUf 18073 4 UmUmAmAmGmAmUmAmA UmGfUmUfGmUfAmGmUmU 18376 APOB_24 mCmAmUmGmAmAfUfCfAmC mAfAmCfUmAfAmUfUmUfGmUf 18074 5 mAmAmAmUmUmAmGmUmU GmAfUmUfCmAfUmGmUmU 18377 APOB_24 mCmAmAmAmUmUfUfCfUmAm mAfU mUfCmGfAmAfU mCfU mAf 18075 6 GmAmUmUmCmGmAmAmU GmAfAmAfUmUfUmGmUmU 18378 APOB_24 mGmCmAmCmAmAfAfCfUmAm mUfC mUfG mAfAmUfU mAfU mAf 18076 7 UmAmAmUmUmCmAmGmA GmUfUmUfGmUfGmCmUmU 18379 APOB_24 mGmAmUmUmUmCfAfAfGmG mUfAmCfAmCfAmAfUmUfCmCf 18077 8 mAmAmUmUmGmUmGmUmA UmUfGmAfAmAfUmCmUmU 18380 APOB_24 mGmAmAmCmAmAfUfCfCmU mUfU mAfAmCfU mCfU mGfAmG 18078 9 mCmAmGmAmGmUmUmAmA fGmAfUmUfGmUfUmCmUmU 18381 APOB_25 mCmCmUmAmCmAfAfCfAmAm mUfAmUfCmUfUmAfAmCfUmUf 18079 0 GmUmUmAmAmGmAmUmA GmUfUmGfUmAfGmGmUmU 18382 APOB_25 mCmAmCmAmAmAfCfAfGmUm mAfAmUfGmUfUmCfAmGfAmCf 18080 1 CmUmGmAmAmCmAmUmU UmGfUmUfUmGfUmGmUmU 18383 APOB_25 mGmGmAmAmAmAfUfGfGmA mUfCmUfUmUfAmGfGmCfUmC 18081 2 mGmCmCmUmAmAmAmGmA fCmAfUmUfUmUfCmCmUmU 18384 APOB_25 mCmCmAmUmGmUfAfGfGmA mUfCmCfAmUfUmUfAmUfUmCf 18082 3 mAmUmAmAmAmUmGmGmA CmUfAmCfAmUfGmGmUmU 18385 APOB_25 mCmUmAmUmCmAfUfAfUmC mAfUmUfUmAfCmAfCmGfGmAf 18083 4 mCmGmUmGmUmAmAmAmU UmAfUmGfAmUfAmGmUmU 18386 APOB_25 mCmCmAmAmAmAfUfAfAmCm mAfUmGfAmUfUmAfAmGfGmU 18084 5 CmUmUmAmAmUmCmAmU fUmAfUmUfUmUfGmGmUmU 18387 APOB_25 mCmUmUmAmCmAfAfCfAmCm mUfUmAfUmCfUmUfUmAfGmU 18085 6 UmAmAmAmGmAmUmAmA fGmUfUmGfUmAfAmGmUmU 18388 APOB_25 mGmAmAmUmUmUfGfAfAmA mAfAmAfAmCfGmAfAmCfUmUf 18086 7 mGmUmUmCmGmUmUmUmU UmCfAmAfAmUfUmCmUmU 18389 APOB_25 mCmUmUmUmCmUfCfUfCmA mUfUmGfUmAfAmUfCmAfUmG 18087 8 mUmGmAmUmUmAmCmAmA fAmGfAmGfAmAfAmGmUmU 18390 APOB_25 mGmUmAmGmAmUfGfAfAmA mUfGmUfCmAfUmUfGmGfUmU 18088 9 mCmCmAmAmUmGmAmCmA fUmCfAmUfCmUfAmCmUmU 18391 APOB_26 mGmUmUmAmAmCfAfAfAmAm mUfUmGfAmGfAmAfUmAfUmUf 18089 0 UmAmUmUmCmUmCmAmA UmUfGmUfUmAfAmCmUmU 18392 APOB_26 mCmAmAmGmUmUfGfAfAmG mAfAmUfAmGfUmCfUmCfCmUf 18090 1 mGmAmGmAmCmUmAmUmU UmCfAmAfCmUfUmGmUmU 18393 APOB_26 mCmUmAmCmCmUfUfAfCmA mUfGmAfUmUfAmUfUmGfUmG 18091 2 mCmAmAmUmAmAmUmCmA fUmAfAmGfGmUfAmGmUmU 18394 APOB_26 mGmUmAmCmUmCfUfAfCmC mUfCmCfUmUfUmAfGmCfGmG 18092 3 mGmCmUmAmAmAmGmGmA fUmAfGmAfGmUfAmCmUmU 18395 APOB_26 mCmAmCmUmCmAfUfUfGmA mUfUmCfAmGfAmAfAmAfUmCf 18093 4 mUmUmUmUmCmUmGmAmA AmAfUmGfAmGfUmGmUmU 18396 APOB_26 mCmCmAmCmAmUfUfCfCmU mUfGmUfAmAfAmGfGmAfAmG 18094 5 mUmCmCmUmUmUmAmCmA fGmAfAmUfGmUfGmGmUmU 18397 APOB_26 mGmUmAmCmCmAfUfAfAmG mAfAmAfAmUfAmUfGmGfCmUf 18095 6 mCmCmAmUmAmUmUmUmU UmAfUmGfGmUfAmCmUmU 18398 APOB_26 mCmAmAmAmAmGfGfUfUmU mAfAmUfAmUfUmAfGmUfAmAf 18096 7 mAmCmUmAmAmUmAmUmU AmCfCmUfUmUfUmGmUmU 18399 APOB_26 mGmAmAmCmUmAfCfGfAmG mUfAmAfAmGfUmCfAmGfCmUf 18097 8 mCmUmGmAmCmUmUmUmA CmGfUmAfGmUfUmCmUmU 18400 APOB_26 mGmAmCmAmUmGfUfUfGmA mAfUmUfUmCfUmUfUmAfUmCf

[1124]

[1125] 18098 9 mUmAmAmAmGmAmAmAmU AmAfCmAfUmGfUmCmUmU 18401 APOB_27 mCmUmUmCmCmUfUfUfAmC mAfAmGfUmCfAmAfUmUfGmUf 18099 0 mAmAmUmUmGmAmCmUmU AmAfAmGfGmAfAmGmUmU 18402 APOB_27 mGmAmAmAmGmAfGfAfUmG mAfGmUfAmAfAmUfUmUfCmAf 18100 1 mAmAmAmUmUmUmAmCmU UmCfUmCfUmUfUmCmUmU 18403 APOB_27 mCmUmCmAmAmGfAfAfUmU mUfUmCfAmUfAmUfGmGfAmAf 18101 2 mCmCmAmUmAmUmGmAmA UmUfCmUfUmGfAmGmUmU 18404 APOB_27 mCmUmUmAmCmAfUfCfCmU mUfUmGfAmUfGmUfUmCfAmG 18102 3 mGmAmAmCmAmUmCmAmA fGmAfUmGfUmAfAmGmUmU 18405 APOB_27 mGmCmAmUmCmUfUfCfGmU mAfGmUfUmGfAmAfAmCfAmCf 18103 4 mGmUmUmUmCmAmAmCmU GmAfAmGfAmUfGmCmUmU 18406 APOB_27 mCmCmAmAmUmAfAfGfAmUm mUfUmGfCmUfAmUfUmGfAmU 18104 5 CmAmAmUmAmGmCmAmA fCmUfUmAfUmUfGmGmUmU 18407 APOB_27 mCmAmUmUmCmCfAfUfCmA mAfAmGfG mAfU mUfU mGfU mG 18105 6 mCmAmAmAmUmCmCmUmU fAmUfGmGfAmAfUmGmUmU 18408 APOB_27 mCmCmAmAmAmGfUfCfCmA mAfUmUfAmAfCmUfCmAfUmGf 18106 7 mUmGmAmGmUmUmAmAmU GmAfCmUfUmUfGmGmUmU 18409 APOB_27 mGmAmUmCmAmAfGfAfAmC mAfAmCfUmAfAmCfAmGfGmUf 18107 8 mCmUmGmUmUmAmGmUmU UmCfUmUfGmAfUmCmUmU 18410 APOB_27 mCmAmGmAmUmAfUfUfAmAm mAfCmAfAmUfUmUfUmGfUmUf 18108 9 CmAmAmAmAmUmUmGmU AmAfUmAfUmCfUmGmUmU 18411 APOB_28 mGmAmUmGmUmGfUfUfAmA mAfAmUfAmUfUmUfUmGfUmUf 18109 0 mCmAmAmAmAmUmAmUmU AmAfCmAfCmAfUmCmUmU 18412 APOB_28 mGmAmUmUmCmCfUfUfUmG mAfCmCfAmAfAmAfGmGfCmAf 18110 1 mCmCmUmUmUmUmGmGmU AmAfGmGfAmAfUmCmUmU 18413 APOB_28 mCmAmUmUmUmGfUfUfUmA mUfAmUfUmUfUmCfAmAfUmAf 18111 2 mUmUmGmAmAmAmAmUmA AmAfCmAfAmAfUmGmUmU 18414 APOB_28 mGmUmAmUmAmUfUfAfAmAm mAfU mAfAmCfU mAfU mCfU mUf 18112 3 GmAmUmAmGmUmUmAmU UmAfAmUfAmUfAmCmUmU 18415 APOB_28 mGmGmUmUmCmAfAfUfCmA mUfAmCfUmUfAmUfAmCfUmGf 18113 4 mGmUmAmUmAmAmGmUmA AmUfUmGfAmAfCmCmUmU 18416 APOB_28 mGmCmAmAmUmGfUfCfCmU mAfCmUfUmGfUmUfGmUfAmG 18114 5 mAmCmAmAmCmAmAmGmU fGmAfCmAfUmUfGmCmUmU 18417 APOB_28 mGmAmCmAmUmAfUfAfUmG mAfAmAfUmUfGmUfAmUfCmAf 18115 6 mAmUmAmCmAmAmUmUmU UmAfUmAfUmGfUmCmUmU 18418 APOB_28 mCmUmAmGmAmUfUfCfGmA mAfUmUfUmGfAmUfAmUfUmCf 18116 7 mAmUmAmUmCmAmAmAmU GmAfAmUfCmUfAmGmUmU 18419 APOB_28 mCmUmAmUmGmUfGfUfUmC mUfGmCfUmUfUmUfGmGfGmA 18117 8 mCmCmAmAmAmAmGmCmA fAmCfAmCfAmUfAmGmUmU 18420 APOB_28 mCmAmAmCmCmUfUfAfAmUm mUfUmGfAmAfAmAfUmCfAmUf 17933 9 GmAmUmUmUmUmCmAmA UmAfAmGfGmUfUmGmUmU 18236 APOB_29 mGmAmUmCmAmAfUfUfUmG mAfUmUfUmUfCmUfUmAfCmAf 18118 0 mUmAmAmGmAmAmAmAmU AmAfUmUfGmAfUmCmUmU 18421 APOB_29 mGmAmUmCmAmGfUfAfUmA mUfAmUfCmUfUmUfAmAfUmAf 18119 1 mUmUmAmAmAmGmAmUmA UmAfCmUfGmAfUmCmUmU 18422 APOB_29 mGmUmUmAmUmGfAfUfUmU mAfAmAfUmCfAmUfGmUfAmAf 18120 2 mAmCmAmUmGmAmUmUmU AmUfCmAfUmAfAmCmUmU 18423 APOB_29 mCmCmAmCmUmUfUfGfGmC mUfU mUfGmGfUmAfU mAfGmC 18121 3 mUmAmUmAmCmCmAmAmA fCmAfAmAfGmUfGmGmUmU 18424 APOB_29 mCmAmCmAmAmGfAfUfUmG mUfUmUfUmCfUmUfGmUfCmA 18122 4 mAmCmAmAmGmAmAmAmA fAmUfCmUfUmGfUmGmUmU 18425 APOB_29 mGmAmUmGmAmAfAfUfUmU mAfAmGfAmUfAmAfGmUfAmAf 18123 5 mAmCmUmUmAmUmCmUmU AmUfUmUfCmAfUmCmUmU 18426 APOB_29 mGmAmUmAmAmAfGfAfAmAm mUfGmAfCmUfUmUfAmAfUmUf 18124 6 UmUmAmAmAmGmUmCmA UmCfUmUfUmAfUmCmUmU APOB_29 mGmAmAmUmUmUfAfAfGmU mUfGmAfAmAfUmCfAmUfAmCf 18125 18427 7 mAmUmGmAmUmUmUmCmA UmUfAmAfAmUfUmCmUmU APOB_29 mCmAmUmAmUmAfUfGfAmU mUfCmAfAmAfUmUfGmUfAmUf 18126 18428 8 mAmCmAmAmUmUmUmGmA CmAfUmAfUmAfUmGmUmU APOB_29 mCmAmAmCmUmAfAfUfAmGm mUfGmUfUmAfUmCfUmUfCmU

[1126]

[1127] 18127 18429 9 AmAmGmAmUmAmAmCmA fAmUfUmAfGmUfUmGmUmU APOB_30 mGmGmAmAmUmCfUfUfAmU mGfGmAfUmCfAmAfAmUfAmUf

[1128]

[1129] 18128 18430 0 mAmUmUmUmGmAmUmCmC AmAfGmAfUmUfCmCmUmU

[1130] Example 8

[1131] Performance of bispecific APOB-DGAT2 in vitro and in vivo mouse study Table 20:

[1132] In vitro knockdown performance of APOB(25)-DGAT2 bispecific and mono siRNAs.

[1133] Primary C57BI6 hepatocytes were plated with RNase-free water (Vehicle) or the indicated concentration of mono siRNAs or APOB(25)-DGAT2 bispecific. 24 hours after plating cells media was changed and cells incubated for a further 24 hours. Cells were lysed in Cells-to-Ct lysis buffer and Apob and Dgat2 relative expression measured by Taqman qPCR, normalised to Gapdh levels within samples and to the average of vehicle treated cells. All data presented as mean ± standard deviation, n=3 per condition.

[1134] Apob (relative expression) Dgat2 (relative expression) Compound 0.1 nM 1 nM 10 nM 0.1 nM 1 nM 10 nM Vehicle 1.00 ± 0.05 1.00 ± 0.06

[1135] APOB mono 0.66 0.36 0.14

[1136] NA

[1137] ± 0.04 ± 0.06 ± 0.01

[1138] DGAT2 mono 0.63 0.27 0.08 NA

[1139] ± 0.03 ± 0.01 ± 0.01 APOB-DGAT2 0.63 0.40 0.14 0.64 0.37 0.12

[1140]

[1141] bispecific ± 0.09 ± 0.02 ± 0.01 ± 0.08 ± 0.03 ± 0.02

[1142] Mouse study testing Bispecific ApoB-DGAT2 siRNA in vivo

[1143] Methodology

[1144] 144 Male C57BL / 6J mice (20-25 g on arrival) were group-housed at the Transpharmation animal facility at the University of Reading. Animals were maintained under a 12 h light / dark cycle, where temperature and humidity are controlled according to Home Office regulations. Mice were given access to standard rodent chow for the duration of the study.

[1145] Bispecifics were formulated in RNAase free PBS to a concentration of 4 mg / mL to provide a dose of 20 mg / kg when given subcutaneously in 5 mL / kg dosing volumes. Monospecifics were formulated in RNAase free PBS to a concentration of 2 mg / mL to provide a dose of 10 mg / kg when given subcutaneously in 5 mL / kg dosing volumes. Mice were weighed prior to compound administration (Day 0) and allocated to groups of 4, 12, 24 or 32. Groups of mice were then injected subcutaneously with either vehicle (RNase free PBS), monospecific siRNA, bispecific siRNAs or control bispecific siRNA. Mice were then returned to their home cages. On Day 1 and twice weekly thereafter mice were weighed and assessed for any overt signs of tolerability issues. On day 21, a subgroup of the mice for certain treatments was re-injected with a second dose of the compound.

[1146] Liver processing for RT-qPCR

[1147] On Day 7, 21, 42 or 64 some or all mice from each treatment group were food deprived for 4 h and then terminally sampled by cardiac puncture under isoflurane. Immediately, after blood sample collection, whole liver tissue was excised and weighed. The snap-frozen liver portion was used for qPCR analysis. Total RNA was extracted from homogenates of snap-frozen liver using QIAGEN RNeasy Mini Kit (74104).

[1148] Duplex RT-qPCR was performed using the ThermoFisher TaqMan Fast 1-Step Master Mix with TaqMan probes forGAPDH (VIC_PL, Assay Id Mm99999915_g1), ApoB (FAM, Assay Id Mm01545150_m1 FAM) or DGAT2 (FAM, Assay Id Mm00499536_m1). Relative quantification (RQ) of target mRNA was determined using the AACT method, where GAPDH was used as internal control and the expression changes of the target gene were normalized to the vehicle control.

[1149] Liver histology: one lobe was removed for possible histology and placed in 5 x volume of neutral-buffered formalin (NBF).

[1150] Blood assays

[1151] Measuring plasma biomarkers; blood samples were taken from the mice from each treatment group 7, 21, 42 or 64 days later by cardiac puncture under isoflurane.

[1152] Blood (>300 pL) was placed into Eppendorf tubes on ice containing 6.5 pL EDTA (93 mg / mL). Following gentle mixing, samples were centrifuged at 10,000 rpm x 3 min and plasma (1 x 30 pL for LDL and HDL, 1 x 20 pL for ApoB, 1 x 20 pL for AST and 1 x 20 pL for triglycerides and rest of sample, collected into separate Eppendorf tubes on dry ice before storing at -20C (until measured by ELISA). Plasma LDL and HDL levels were measured using a CrystalChem mouse LDL assay kit (Cat no # 79980) and CrystalChem mouse HDL assay kit (Cat no # 79990), respectively. Verification of LDL calibration curves were ensured by use of a #79983 mouse LDL control. Plasma Triglyceride levels were measured using a Cayman 10010303 kit (Cambridge Bioscience).

[1153] Plasma ApoB levels were measured using an Abeam mouse Apo B ELISA Kit (ab230932).

[1154] AST was measured using an AbCam mouse AST (ab263882) ELISA kit. Plasma Angptl3 levels were measured using an R&D systems, cat. no. MANL30 ELISA kit.

[1155] Table 21

[1156] In vivo knockdown performance of APOB_25-DGAT2 bispecific and mono siRNAs.

[1157] Healthy C57BI6 mice were injected subcutaneously with RNase-free PBS (Vehicle), 10 mg / kg of the indicated mono siRNA or 20 mg / kg of APOB_25-DGAT2 bispecific at day 0. A subgroup of mice received an additional dose of compounds at day 21. Mice were sacrificed and livers collected on the indicated days for RNA isolation. Apob and Dgat2 relative expression was measured by TaqMan qPCR, normalised to Gapdh levels within samples and to the average of vehicle treated mice. All data presented as mean ± standard deviation.

[1158] Apob (relative expression) Dgat2 (relative expression) Compound Day 7 Day 21 Day 42 Day 42 Day 7 Day 21 Day 42 Day 42

[1159] (n=8) (n=8) (n=4) 2nd (n=8) (n=8) (n=4) 2nd dose dose (n=4) (n=4) Vehicle 1.00 1.00 1.00 1.00 1.00 1.00

[1160] ± 0.09 ± 0.09 ± 0.15 ± 0.13 ± 0.8 ± 0.05 APOB 0.10 0.07 0.17 0.09 NA NA NA NA mono ± 0.03 ± 0.01 ± 0.09 ± 0.07

[1161] DGAT2 NA NA NA NA 0.25 0.30 0.72 0.33 mono ± 0.3 ± 0.05 ± 0.07 ± 0.02 APOB- 0.07 0.07 0.22 0.07 0.15 0.26 0.67 0.27 DGAT2 ± 0.01 ± 0.01 ± 0.02 ± 0.01 ± 0.03 ± 0.03 ± 0.03 ± 0.03

[1162]

[1163] bispecific Table 22: DGAT2 sequence screening in HepG2 cells. HepG2 cells were transfected with the indicated concentration of DGAT2 siRNAs, using RNAiMAX lipofectamine, in triplicate. 48-hours after transfection cells were lysed and RT-qPCR performed to measure the relative expression level of DGAT2, normalised to GAPDH gene expression levels. Relative knockdown of DGAT2 was calculated against cells treated with RNAiMAX and no siRNA.

[1164] 10 nM

[1165] Overall 0.1 nM 1 nM KD

[1166] rank SEQ ID KD (%) KD (%) (%) Sense Antisense 13 92 94 94 GUCUGUGG UUUUAAAUA GUUAUUUAA ACCCACAGA

[1167] 1 AA CUU

[1168] 24 89 94 96 GCUCUGUAA ACUUCCAAA AUUUGGAAG UUUACAGAG

[1169] 2 U CUU

[1170] 26 91 93 94 UGGAGAGAA GUACACUUC UGAAGUGUA AUUCUCUCC

[1171] 3 C AUU

[1172] 79 90 93 94 UGGGUGUCU AAUAACCCA GUGGGUUAU CAGACACCC

[1173] 4 U AUU

[1174] 31 89 93 93 CUGUGGGUU UCUUUUAAA AUUUAAAAG UAACCCACA

[1175] 5 A GUU

[1176] 65 91 94 92 UUGCUCUGU UUCCAAAUU AAAUUUGGA UACAGAGCA

[1177] 6 A AUU

[1178] 1 87 93 93 CUGUAAAUU GACACUUCC UGGAAGUGU AAAUUUACA

[1179] 8 C GUU

[1180] 45 83 93 95 CCAGGAACU CCAAAGAUA AUAUCUUUG UAGUUCCUG

[1181] 7 G GUU

[1182] 50 88 92 94 GGGUGUCU AAAUAACCC GUGGGUUAU ACAGACACC

[1183] 9 UU CUU

[1184] 55 89 92 93 GUGUCUGUG UUAAAUAAC GGUUAUUUA CCACAGACA

[1185] 10 A CUU

[1186] 47 87 92 93 UCCUCAUGU CAGAAUAUG ACAUAUUCU UACAUGAGG

[1187] 11 G AUU

[1188] 15 85 92 92 CCUUUGGAG ACUUCAUUC AGAAUGAAG UCUCCAAAG

[1189] 12 U GUU

[1190] 80 79 93 94 UCUGUGGGU CUUUUAAAU UAUUUAAAA AACCCACAG

[1191] 13 G AUU

[1192] 11 77 92 96 CGAUGGGUC ACUUCUUCU

[1193]

[1194] 14 CAGAAGAAG GGACCCAUC U GUU

[1195] 57 81 90 96 UCGCUGUGC GUGAAGUAG UCUACUUCA AGCACAGCG

[1196] 16 C AUU

[1197] 61 83 91 93 UCAUGGGUG AACCCACAG UCUGUGGGU ACACCCAUG

[1198] 15 U AUU

[1199] 14 83 92 93 UCACUUGGC UCAAACACC UGGUGUUUG AGCCAAGUG

[1200] 17 A AUU

[1201] 3 90 92 88 CCACCAGGA AAGAUAUAG ACUAUAUCU UUCCUGGUG

[1202] 18 U GUU

[1203] 8 90 91 88 UCUGUAAAU ACACUUCCA UUGGAAGUG AAUUUACAG

[1204] 19 U AUU

[1205] 39 88 89 91 GGUGUCUGU UAAAUAACC GGGUUAUUU CACAGACAC

[1206]

[1207] 20 A CUU Sense modification pattern - mmmmmmfffmmmmmmmmmm

[1208] Antisense modification pattern - mfmfmfmfmfmfmfmfmfm + mUrnll

[1209] m - 2'-0-methyl; f - 2'-fluoro; KD - knockdown

[1210] Table 23

[1211] Effect of APOB-DGAT2 bispecific and mono siRNAs in vivo on plasma markers.

[1212] Healthy C57BI6 mice were injected subcutaneously with RNase-free PBS (Vehicle), 10 mg / kg of the indicated mono siRNA or 20 mg / kg of APOB-DGAT2 bispecific at day 0. A subgroup of mice received an additional dose of compounds at day 21. Mice were sacrificed and blood collected into EDTA. Anti-coagulated blood was centrifuged at 10,000 rpm for 3 minutes, plasma aliquoted and stored at -70°C. ELISAs / colorimetric assays were used to measure the indicated plasma markers. APOB (Apolipoprotein B, mg / dL), LDL-C (Low-density lipoprotein-cholesterol, mg / dL), TGs (triglycerides, mg / dL), HDL-C (High-density lipoprotein-cholesterol, mg / dL), AST (Aspartate aminotransferase, .g / dL). All data presented as mean ± standard deviation. Data analysed by one-way ANOVA with Dunnett’s multiple comparison test vs. Vehicle for each time point: n.s. (no significant difference), * (p-value < 0.05), ** (p-value < 0.005), *** (p-value < 0.0005).

[1213] Vehicle APOB mono DGAT2 mono APOB-DGAT2 bispecific Da Da Da Da Da Da Da Da Da Da Da Da Da Da Da y y y y y y y y y y y y y y y 7 21 42 7 21 42 42 7 21 42 42 7 21 42 42 (n= (n= (n= (n= (n= (n= 2nd (n= (n= (n= 2nd (n= (n= (n= 2nd

[1214]

[1215] 8) 8) 4) 8) 8) 4) do 8) 8) 4) do 8) 8) 4) do se se se (n= (n= (n= 4) 4) 4) AP 30. 19. 23. 0.3 0.4 0.9 0.1 34. 34. 25. 29. 0.6 0.7 2.5 0.1 OB 4 6 4 ± ± 3 6 7 1 3 0 ± ± ± ± ± ± ± 0.2 0.2 ± ± ± ± ± ± 0.3 0.5 0.9 0.1 13. 2.9 3.0 *** *** 1.0 0.3 12. 6.6 5.0 2.6 *** *** *** *** 0 *** 1 8 *** n.s.

[1216] *** n.s.

[1217] LD 84. 84. 108 12. 12. 37. 20. 48. 51. 93. 75. 11. 14. 36. 15. L-C 8 3 ± 7 4 7 4 4 6 0 3 9 5 5 6 ± ± 6.6 ± ± ± ± ± ± ± ± ± ± ± ± 7.1 10. 2.1 3.1 7.5 2.5 11. 11. 13. 3.1 2.7 2.0 6.0 8.1 4 *** *** *** *** 6 9 3 *** *** *** *** ***

[1218] *** *** n.s.

[1219] TG 58. 65. 76. 24. 35. 27. 19. 63. 54. 69. 67. 22. 27. 32. 18. s 3 1 1 1 8 3 4 2 7 7 6 4 3 4 1 ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± 14. 15. 18. 4.5 14. 3.9 1.7 13. 12. 13. 10. 2.6 8.2 8.3 5.0 0 8 8 *** 0 *** *** 9 3 0 4 *** *** *** ***

[1220] ** n.s. n.s. n.s. n.s.

[1221] HD 41. 31. 34. 11. 12. 22. 16. 27. 25. 34. 38. 12. 11. 24. 9.2 L-C 1 9 7 3 6 7 0 4 4 7 7 7 8 2 ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± 3.1 21. 14. 5.8 5.3 5.4 0.8 5.2 13. 8.1 14. 21. 9.6 3.7 6.8 n.s.

[1222] 1 9 *** ** n.s. n.s. 5 n.s. 0 4 ** *** n.s.

[1223] n.s. n.s. n.s.

[1224] AS 48. 45. 42. 72. 77. 22. 32. 75. 59. 31. 31. 44. 45. 57. 41. T 6 5 1 4 8 8 9 5 5 3 9 1 9 8 0 ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± 25. 36. 34. 53. 78. 7.4 23. 58. 60. 12. 17. 28. 39. 60. 29.

[1225] 4 8 9 0 6 n.s. 2 1 8 2 2 4 8 8 6

[1226]

[1227] n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s.

[1228] Table 24

[1229] Effect of APOB-DGAT2 bispecific and mono siRNAs on liver triglycerides.

[1230] Healthy C57BI6 mice were injected subcutaneously with RNase-free PBS (Vehicle), 10 mg / kg of the indicated mono siRNA or 20 mg / kg of APOB-DGAT2 bispecific at day 0. A subgroup of mice received an additional dose of compounds at day 21. Mice were sacrificed and livers collected on the indicated days. Lipids from liver tissue were solubilised in NP-40, triglycerides measured using a colorimetric assay and normalised to the mass of tissue lysed. All data presented as mean ± standard deviation. Data analysed by one-way ANOVA with Dunnett’s multiple comparison test vs. APOB mono for each time point: n.s. (no significant difference), ** (p-value < 0.005), *** (p-value < 0.0005). Liver triglycerides (mg / g)

[1231] Compound (dose) Day 7 Day 21 Day 42 Day 42

[1232] (n=8) (n=8) (n=4) 2nddose (n=4) Vehicle 8.4 ± 0.7 6.5 ± 0.4 4.7 ± 0.4

[1233] *** *** *** APOB mono 13.9 ± 1.0 13.5 ± 1.2 12.4 ± 1.9 12.2 ± 1.2 DGAT2 mono 6.0 ± 0.4 5.8 ± 1.2 5.0 ± 0.3 5.2 ± 0.5

[1234] *** *** *** *** APOB-DGAT2 9.7 ± 1.5 8.6 ± 1.0 10.0 ± 2.2 8.5 ± 1.2

[1235] *** *** **

[1236]

[1237] bispecific n.s.

Claims

CLAIMS1. A nucleic acid molecule comprising:i) a first nucleic acid comprising a double stranded inhibitory ribonucleic acid (RNA) molecule comprising a sense and an antisense strand designed with reference to a nucleotide sequence comprising a gene to be silenced and wherein there is provided a first single stranded deoxyribonucleic acid (DNA) molecule conjugated to either the 5’ or 3’ end of said sense or antisense strand; andi) a second nucleic acid comprising a double stranded inhibitory ribonucleic acid (RNA) molecule comprising a sense and an antisense strand designed with reference to a different or the same gene to be silenced as set forth in i) above and wherein there is provided a second single stranded deoxyribonucleic acid (DNA) molecule conjugated to either the 5’ or 3’ end of said sense or antisense strand wherein the second single stranded deoxyribonucleic acid (DNA) molecule is substantially complementary to the first single stranded deoxyribonucleic acid (DNA) molecule set forth in i) above and anneals by complementary base pairing to form a double stranded DNA linker that links the first and second double stranded inhibitory ribonucleic acid (RNA) molecules wherein said DNA linker molecule is notCGAAGCGCCCTACTCCACT (SEQ ID NO: 17155) GCTTCGCGGGATGAGGTGA, (SEQ ID NO: 17156)wherein the DNA linker molecule comprises a nucleotide sequence having a melting temperature (TM) that is about 73°C + / - 5%.

2. The nucleic acid molecule according to claim 1 wherein said DNA linker molecule comprises a nucleotide sequence wherein the TM is about 69°C to 76°C.

3. The nucleic acid molecule according to claims 1 or 2 wherein said DNA linker molecule comprises a nucleotide sequence wherein the TM is about 73°C.

4. The nucleic acid molecule according to any one of claims 1 to 3 wherein said first single stranded deoxyribonucleic acid (DNA) molecule comprises the nucleotide sequence: 5’ CGAAGCG 3’.

5. The nucleic acid molecule according to any one of claims 1 to 4 wherein said single stranded DNA comprises the nucleotide sequence 5’ CGAAGCGCCCTACTCCACT 3’ (SEQ ID NO: 17155).

6. The nucleic acid molecule according to any one of claims 1 to 4 wherein said complementary single stranded DNA comprises the nucleotide sequence 5’ AGTGGAGTAGGGCGCTTCG 3’ (SEQ ID NO: 17156).

7. The nucleic acid molecule according to any one of claims 1 to 6 wherein said single stranded DNA comprises the nucleotide sequence 5’ CGAAGCGCCCTACTCCACT 3’ (SEQ ID NO: 17155) and is attached to the 5’ end of the sense nucleotide sequence.

8. The nucleic acid molecule according to any one of claims 1 to 6 wherein said single stranded DNA comprises the nucleotide sequence 5’ CGAAGCGCCCTACTCCACT 3’ (SEQ ID NO: 17155) and is attached to the 5’ end of the antisense nucleotide sequence.

9. The nucleic acid molecule according to any one of claims 1 to 6 wherein said complementary single stranded DNA comprises the nucleotide sequence 5’ AGTGGAGTAGGGCGCTTCG 3’ (SEQ ID NO: 17156) and is attached to the 5’ end of the sense nucleotide sequence.

10. The nucleic acid molecule according to any one of claims 1 to 6 wherein said complementary single stranded DNA comprises the nucleotide sequence 5’ AGTGGAGTAGGGCGCTTCG 3’ (SEQ ID NO: 17156) and is attached to the 5’ end of the antisense nucleotide sequence.

11. The nucleic acid molecule according to any one of claims 1 to 4 wherein said first single stranded DNA molecule comprises a nucleotide sequence selected from the group: SEQ ID NO: 1 to SEQ ID NO: 6170.

12. The nucleic acid molecule according to claim 11 wherein said second single stranded complementary DNA molecule is selected from the group: SEQ ID NO: 6171 to SEQ ID NO: 12340 and is fully complementary to said first single stranded DNA molecule as set forth in SEQ ID NO: 1 to SEQ ID NO: 6170 and is a stable double stranded DNA linker molecule.

13. The nucleic acid molecule according to any one of claims 1 to 12 wherein said stable double stranded DNA linker molecule has a TM of about 73°C.

14. The nucleic acid molecule according to any one of claims 1 to 13 wherein said first or second gene to be silenced is the Apo B gene.

15. The nucleic acid molecule according to claim 14 wherein said Apo B gene comprises a nucleotide sequence set forth in SEQ ID NO: 12341 wherein said double stranded inhibitory RNA is 19-23 nucleotides in length.

16. The nucleic acid molecule according to any one of claims 1 to 13 wherein said first or second gene to be silenced is PCSK9.

17. The nucleic acid molecule according to claim 16 wherein said PCSK9 gene comprises a nucleotide sequence set forth in SEQ ID NO: 12342 wherein said double stranded inhibitory RNA is 19-23 nucleotides in length.18 . The nucleic acid molecule according to any one of claims 1 to 13 wherein said first or second gene to be silenced is lipoprotein A (Lp(a)).

19. The nucleic acid molecule according to claim 18 wherein said lipoprotein A gene comprises a nucleotide sequence set forth in SEQ ID NO: 12343 wherein said double stranded inhibitory RNA is 19-23 nucleotides in length.

20. The nucleic acid molecule according to any one of claims 1 to 13 wherein said first or second gene to be silenced is angiotensinogen.

21. The nucleic acid molecule according to claim 20 wherein said angiotensinogen gene comprises a nucleotide sequence set forth in SEQ ID NO: 12344 wherein said double stranded inhibitory RNA is 19-23 nucleotides in length.

22. The nucleic acid molecule according to any one of claims 1 to 13 wherein said first or second gene to be silenced is Apo CHI.

23. The nucleic acid molecule according to claim 22 wherein said Apo CHI gene comprises a nucleotide sequence set forth in SEQ ID NO: 12345 wherein said double stranded inhibitory RNA is 19-23 nucleotides in length.

24. The nucleic acid molecule according to any one of claims 1 to 13 wherein said first or second gene to be silenced is DGAT2.

25. The nucleic acid molecule according to claim 24 wherein said DGAT2 gene comprises a nucleotide sequence set forth in SEQ ID NO:12346 wherein said double stranded inhibitory RNA is 19-23 nucleotides in length.

26. The nucleic acid molecule according to any one of claims 1 to 13 wherein said first or second gene to be silenced is ANGPTL3.

27. The nucleic acid molecule according to claim 26 wherein said ANGPTL3 gene comprises a nucleotide sequence set forth in SEQ ID NO: 17159 wherein said double stranded inhibitory RNA is 19-23 nucleotides in length.

28. The nucleic acid molecule according to any one of claims 1 to 13 wherein said first or second gene to be silenced is ANGPTL4.

29. The nucleic acid molecule according to claim 28 wherein said ANGPTL4 gene comprises a nucleotide sequence set forth in SEQ ID NO: 17160 wherein said double stranded inhibitory RNA is 19-23 nucleotides in length.

30. The nucleic acid molecule according to any one of claims 1 to 29 wherein said first and / or said second double stranded inhibitory RNA molecule comprises modified nucleotides and / or modified sugar(s).

31. The nucleic acid molecule according to any one of claims 1 to 30 wherein said nucleic acid molecule is covalently linked to / V-acetylgalactosamine.

32. A pharmaceutical composition comprising a nucleic acid molecule according to any one of claims 1 to 31.

33. A nucleic acid molecule or a pharmaceutical composition according to any one of claims 1 to 32 for use in the treatment or prevention of a subject that has or is predisposed to hypercholesterolemia.

34. A nucleic acid molecule comprising:i) a first nucleic acid comprising a double stranded inhibitory ribonucleic acid (RNA) molecule comprising a sense and an antisense strand with reference to a nucleotide sequence comprising a cardiovascular disease associated gene to be silenced wherein said cardiovascular disease gene is apolipoprotein B (Apo B) and wherein there is provided a first single stranded deoxyribonucleic acid (DNA) molecule conjugated to either the 5’ or 3’ end of said sense or antisense strand; and ii) a second nucleic acid comprising a double stranded inhibitory ribonucleic acid (RNA) molecule comprising a sense and an antisense strand with reference to a different cardiovascular disease associated gene to be silenced wherein said cardiovascular disease gene is diacylglycerol O acyitransferase 2 (DGAT2) and wherein there is provided a second single stranded deoxyribonucleic acid (DNA) molecule conjugated to either the 5’ or 3’ end of said sense or antisense strand wherein the second single stranded deoxyribonucleic acid (DNA) molecule is substantially complementary to the first single stranded deoxyribonucleic acid (DNA) molecule set forth in i) above and anneals by complementary base pairing to form a double stranded DNA linker that links the first and second double stranded inhibitory ribonucleic acid (RNA) molecules wherein said DNA linker molecule comprises a nucleotide sequence having a melting temperature (TM) that is 73°C + / - 5%.

35. The nucleic acid molecule according to claim 34 wherein said DNA linker molecule comprises a nucleotide sequence wherein the TM is about 69°C to 76°C36. The nucleic acid molecule according to claims 34 or 35 wherein said DNA linker molecule comprises a nucleotide sequence wherein the TM is about 73°C.

37. The nucleic acid molecule according to any one of claims 34 to 36 wherein said first single stranded deoxyribonucleic acid (DNA) molecule comprises the nucleotide sequence: 5’ CGAAGCG 3’.38 The nucleic acid molecule according to any one of claims 34 to 37 said single stranded DNA comprises the nucleotide sequence 5’ CGAAGCGCCCTACTCCACT 3’ (SEQ ID NO: 17155).

39. The nucleic acid molecule according to any one of claims 34 to 38 wherein said complementary single stranded DNA comprises the nucleotide sequence 5’ AGTGGAGTAGGGCGCTTCG 3’ (SEQ ID NO: 17156).

40. The nucleic acid molecule according to any one of claims 34 to 37 wherein said first single stranded DNA molecule comprises a nucleotide sequence selected from the group: SEQ ID NO: 1 to SEQ ID NO: 6170.

41. The nucleic acid molecule according to claim 40 wherein said second single stranded complementary DNA molecule is selected from the group: SEQ ID NO: 6171 to SEQ ID NO: 12340 and is fully complementary to said first single stranded DNA molecule as set forth in SEQ ID NO: 1 to SEQ ID NO: 6170 and is a stable double stranded DNA linker molecule.

42. The nucleic acid molecule according to any one of claims 34 to 41 wherein said Apo B and / or DGAT2 double stranded inhibitory RNA comprises or consists of a modified sense and / or antisense nucleotide sequence.

43. The nucleic acid molecule according to claim 42 wherein said Apo B and / or DGAT2 double stranded inhibitory RNA is modified and comprises one or more 2'-O-methyl moieties.

44. The nucleic acid molecule according to claims 42 or 43 wherein said Apo B and / or DGAT2 double stranded inhibitory RNA is modified and comprises one or more 2'-deoxy-2'-fluoro moieties.

45. The nucleic acid molecule according to any one of claims 42 to 44 wherein said sense nucleotide sequence is modified wherein said modification pattern comprises the following:mmmmmmfffmmmmmmmmmmwherein m - 2'-O-methyl and f - 2'-deoxy-2'-fluoro.

46. The nucleic acid molecule according to any one of claims 42 to 45 wherein said antisense nucleotide sequence is modified wherein said modification patter comprises the following:mfmfmfmfmfmfmfmfmfm + mUrnllwherein m - 2'-O-methyl and f - 2'-deoxy-2'-fluoro.

47. The nucleic acid molecule according to any one of claims 34 to 46 wherein said DGAT2 double stranded inhibitory RNA comprises a sense nucleotide sequence set forth in SEQ IDs presented in Table 16 wherein said double stranded inhibitory RNA is 19-23 nucleotides in length.

48. The nucleic acid molecule according to any one of claims 34 to 47 wherein said DGAT2 double stranded inhibitory RNA comprises an antisense nucleotide sequence set forth in SEQ IDs presented in Table 16 wherein said double stranded inhibitory RNA is 19-23 nucleotides in length.

49. The nucleic acid molecule according to any one of claims 34 to 48 said DGAT2 double stranded inhibitory RNA comprises a sense nucleotide sequence set forth in SEQ IDs presented in Table 17 wherein said double stranded inhibitory RNA is 19-23 nucleotides in length.

50. The nucleic acid molecule according to any one of claims 34 to 49 wherein said DGAT2 double stranded inhibitory RNA comprises an antisense nucleotide sequence set forth in SEQ IDs presented in Table 17 wherein said double stranded inhibitory RNA is 19-23 nucleotides in length.

51. The nucleic acid molecule according to any one of claims 34 to 50 wherein said APOB double stranded inhibitory RNA comprises a sense nucleotide sequence set forth in SEQ IDs presented in Table 18 wherein said double stranded inhibitory RNA is 19-23 nucleotides in length.

52. The nucleic acid molecule according to any one of claims 34 to 51 wherein said APOB double stranded inhibitory RNA comprises an antisense nucleotide sequence set forth in SEQ IDs presented in Table 18 wherein said double stranded inhibitory RNA is 19-23 nucleotides in length.

53. The nucleic acid molecule according to any one of claims 34 to 52 wherein said APOB double stranded inhibitory RNA comprises a sense nucleotide sequence set forth in SEQ IDs presented in Table 19 wherein said double stranded inhibitory RNA is 19-23 nucleotides in length.

54. The nucleic acid molecule according to any one of claims 34 to 53 wherein said APOB double stranded inhibitory RNA comprises an antisense nucleotide sequence set forth in SEQ IDs presented in Table 19 wherein said double stranded inhibitory RNA is 19-23 nucleotides in length.

55. The nucleic acid molecule according to claim 42 wherein said double stranded inhibitory RNA comprises sense and antisense nucleotide sequences linked by a double stranded DNA linker wherein said sense nucleotide sequence is:5’_CGAAGCGCCCTACTCCACTmC*mC*mAmAmUmUfUfCfCmCmUmGmUmGmGmA mU*mC*mll / Gal3C2 / 3’; and (SEQ ID NO: 17238)said antisense nucleotide sequence is:AGTGGAGTAGGGCGCTTCGmG*mU*mCmAmUmGmGmGfUfGfUmCmUmGmUmGm G mGmU*mU*mA / Gal3C2 / 3.’ (SEQ ID NO: 17239)56. The nucleic acid molecule according to claim 42 wherein said double stranded inhibitory RNA comprises sense and antisense nucleotide sequences linked by a double stranded DNA linker wherein said sense nucleotide sequence is:5’_CGAAGCGTAGCCGGGGGAAmC*mC*mAmAmUmUfUfCfCmCmUmGmUmGmGmA mU*mC*mll / Gal3C2 / 3’ (SEQ ID NO: 17240)andsaid antisense nucleotide sequence is:5’TTCCCCCGGCTACGCTTCGmG*mU*mCmAmUmGmGmGfUfGfUmCmUmGmUmGm G mGmU*mll*mA / Gal3C2 / 3’. (SEQ ID NO: 17241)57. The nucleic acid molecule according to claim 42 wherein said double stranded inhibitory RNA comprises sense and antisense nucleotide sequences linked by a double stranded DNA linker wherein said sense nucleotide sequence is:5’_CGAAGCGTGACGGGGTCGAmC*mC*mAmAmUmUfUfCfCmCmUmGmUmGmGmA mU *mC*mll / Gal3C2 / 3’ (SEQ ID NO: 17242)and said antisense nucleotide sequence is:TCGACCCCGTCACGCTTCGmG*mU*mCmAmUmGmGmGfUfGfUmCmUmGmUmGmG m GmU*mU*mA / Gal3C2 / 3’. (SEQ ID NO: 17243)58. The nucleic acid molecule according to claim 42 wherein said double stranded inhibitory RNA comprises sense and antisense nucleotide sequences linked by a double stranded DNA linker wherein said sense nucleotide sequence is:5’_CGAAGCGTGACCGGGTCGAmC*mC*mAmAmUmUfUfCfCmCmUmGmUmGmGmA mU *mC*mll / Gal3C2 / 3’ (SEQ ID NO: 17244)and said antisense nucleotide sequence is:5’TCGACCCGGTCACGCTTCGmG*mU*mCmAmUmGmGmGfUfGfUmCmUmGmUmGm G mGmU*mU*mA / Gal3C2 / 3’. (SEQ ID NO: 17245)59. The nucleic acid molecule according to claim 42 wherein said double stranded inhibitory RNA comprises sense and antisense nucleotide sequences linked by a double stranded DNA linker wherein said sense nucleotide sequence is:5’_CGAAGCGCCCTACTCCACTmC*mC*mUmGmGmAmCmAfUfUfCmAmGmAmAmCm AmAmG*mA*mA / Gal3C2 / 3’ (SEQ ID NO: 17246)and said antisense nucleotide sequence is:5’ AGTGGAGTAGGGCGCTTCGmU*mG*mGmGmUmUmAfUfUfUmAfAmAmAmGmA* mA*mA / Gal3C2 / 3’. (SEQ ID NO: 17247)60. The nucleic acid molecule according to any one of claims 34 to 59 wherein said nucleic acid molecule is covalently linked to / V-acetylgalactosamine.

61. A treatment regimen for use in the treatment or prevention of at least one cardiovascular disease comprising administration of a first and second double stranded inhibitory RNA molecule wherein said first double stranded inhibitory RNA molecule is designed with reference to a cardiovascular gene target to be silenced and wherein said second double stranded inhibitory RNA molecule is designed with reference to a different cardiovascular gene target to be silenced wherein said at least first and second double stranded inhibitory RNA molecules are co-administered as simultaneous, sequential, or temporally separate effective dosages to a subject.

62. The treatment regimen according to claim 61 wherein said first and / or said second double stranded inhibitory RNA molecule comprises modified nucleotides and / or modified sugar(s).

63. The treatment regimen according to claim 61 or 62 wherein said cardiovascular gene to be silenced is apolipoprotein B (ApoB).

64. The treatment regimen according to claim 63 wherein said Apo B gene comprises a nucleotide sequence set forth in SEQ ID NO: 12341 wherein said double stranded inhibitory RNA is 19-23 nucleotides in length.

65. The treatment regimen according to claim 61 or claim 62 wherein said cardiovascular gene to be silenced is DGAT2.

66. The treatment regimen according to claim 65 wherein said DGAT2 gene comprises a nucleotide sequence set forth in SEQ ID NO: 12346 wherein said double stranded inhibitory RNA is 19-23 nucleotides in length.

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