Polynucleotides encoding low density lipoprotein receptor
First Claim
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1. A polynucleotide encoding a variant low density lipoprotein receptor (LDLR) wherein the variant LDLR comprises at least one amino acid substitution in the EGF-A domain which corresponds to the sequence of amino acid 314 to amino acid 353 of SEQ ID NO:
- 43 and at least two amino acid substitutions in the intracellular domain which corresponds to the sequence of amino acid 811 to amino acid 860 of SEQ ID NO;
43, wherein the polynucleotide comprises;
A. (a) a first region of linked nucleosides encoding a polypeptide comprising the variant LDLR;
B. (b) a first flanking region located 5′
relative to said first region comprising at least one 5′
terminal cap;
C. (c) a second flanking region located 3′
relative to said first region comprising a 3′
tailing sequence of linked nucleosides; and
D. wherein said polynucleotide is a mRNA comprising, at least one chemically modified nucleoside; and
wherein the variant LDLR comprises an amino acid sequence selected from the group consisting of;
SEQ ID NO;
50, SEQ ID NO;
51, SEQ ID NO;
52, SEQ ID NO;
53, SEQ ID NO;
724, SEQ ID NO;
725, SEQ ID NO;
726, and SEQ ID NO;
727; and
/or the variant LDLR comprises an amino acid substitution in the intracellular domain corresponding to amino acid 816 of SEQ ID NO;
43, amino acid 830 of SEQ ID NO;
43, amino acid 839 of SEQ ID NO;
43, or any combination thereof.
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Abstract
The invention relates to compositions and methods for the preparation, manufacture and therapeutic use of polynucleotide molecules encoding low density lipoprotein receptor comprising at least one mutation (e.g., an LDLR signally enhancing mutation).
893 Citations
13 Claims
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1. A polynucleotide encoding a variant low density lipoprotein receptor (LDLR) wherein the variant LDLR comprises at least one amino acid substitution in the EGF-A domain which corresponds to the sequence of amino acid 314 to amino acid 353 of SEQ ID NO:
- 43 and at least two amino acid substitutions in the intracellular domain which corresponds to the sequence of amino acid 811 to amino acid 860 of SEQ ID NO;
43, wherein the polynucleotide comprises;A. (a) a first region of linked nucleosides encoding a polypeptide comprising the variant LDLR; B. (b) a first flanking region located 5′
relative to said first region comprising at least one 5′
terminal cap;C. (c) a second flanking region located 3′
relative to said first region comprising a 3′
tailing sequence of linked nucleosides; andD. wherein said polynucleotide is a mRNA comprising, at least one chemically modified nucleoside; and wherein the variant LDLR comprises an amino acid sequence selected from the group consisting of;
SEQ ID NO;
50, SEQ ID NO;
51, SEQ ID NO;
52, SEQ ID NO;
53, SEQ ID NO;
724, SEQ ID NO;
725, SEQ ID NO;
726, and SEQ ID NO;
727; and
/or the variant LDLR comprises an amino acid substitution in the intracellular domain corresponding to amino acid 816 of SEQ ID NO;
43, amino acid 830 of SEQ ID NO;
43, amino acid 839 of SEQ ID NO;
43, or any combination thereof. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13)
- 43 and at least two amino acid substitutions in the intracellular domain which corresponds to the sequence of amino acid 811 to amino acid 860 of SEQ ID NO;
Specification