Compositions and methods for silencing apolipoprotein B
AssigneeProtiva Biotherapeutics, Inc.
InventorsAmy C. H. Lee, Adam Judge, Marjorie Robbins, Ed Yaworski, Ian MacLachlan
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Abstract
The present invention provides compositions and methods for the delivery of interfering RNAs that silence APOB expression to liver cells. In particular, the nucleic acid-lipid particles provide efficient encapsulation of nucleic acids and efficient delivery of the encapsulated nucleic acid to cells in vivo. The compositions of the present invention are highly potent, thereby allowing effective knock-down of APOB at relatively low doses. In addition, the compositions and methods of the present invention are less toxic and provide a greater therapeutic index compared to compositions and methods previously known in the art.
Claims26
A nucleic acid-lipid particle comprising:
- (a) an siRNA that silences Apolipoprotein B (APOB) expression, wherein the siRNA consists of the following sense and antisense strand sequences:
- 5′-AGUGUCAUCACACUGAAUACC-3′ (SEQ ID NO:4)
- 3′-GUUCACAGUAGUGUGACUUAU-5′ (SEQ ID NO:11), wherein the bolded nucleotides are 2′OMe nucleotides;
- (b) a cationic lipid having the following structure:
- or salts thereof, wherein:
- R1 and R2 are either the same or different and are independently optionally substituted C12-C24 alkyl, optionally substituted C12-C24 alkenyl, optionally substituted C12-C24 alkynyl, or optionally substituted C12-C24 acyl;
- R3 and R4 are either the same or different and are independently optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, or optionally substituted C2-C6 alkynyl or R3 and R4 may join to form an optionally substituted heterocyclic ring of 4 to 6 carbon atoms and 1 or 2 heteroatoms chosen from nitrogen and oxygen;
- R5 is either absent or hydrogen or C1-C6 alkyl to provide a quaternary amine;
- m, n and p are either the same or different and are independently either 0, 1 or 2, with the proviso that m, n, and p are not simultaneously 0;
- q is 0, 1, 2, 3, or 4;
- Y and Z are either the same or different and are independently O, S, or NH;
- and
- (c) a non-cationic lipid.
An siRNA that silences Apolipoprotein B (APOB) expression consisting of the following sense and antisense strand sequences:
- 5′-AGUGUCAUCACACUGAAUACC-3′
- (SEQ ID NO:
- 4)
- 3′-GUUCACAGUAGUGUGACUUAU-5′,
- (SEQ ID NO:
- 11)
- wherein the bolded nucleotides are 2′OMe nucleotides.
Dependencies are inferred from the claim text.