Peptide-based in vivo siRNA delivery system
First Claim
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1. A conjugate delivery system composition for delivering an RNA interference polynucleotide to a liver cell in vivo comprising:
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RNAi-A and Melittin-(L-Gal)x wherein,Melittin is a melittin peptide,L is physiologically labile reversible linkage wherein cleavage of L-Gal restores an amine on Melittin,Gal is an Asialoglycoprotein Receptor (ASGPr) ligand,x is an integer having a value greater than 80% of primary amines of Melittin,RNAi is an RNA interference polynucleotide, andA is either a hydrophobic group having at least 20 carbon atoms or a galactose cluster.
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Abstract
The present invention is directed compositions for targeted delivery of RNA interference (RNAi) polynucleotides to hepatocytes in vivo. Targeted RNAi polynucleotides are administered together with co-targeted melittin delivery peptides. Delivery peptides provide membrane penetration function for movement of the RNAi polynucleotides from outside the cell to inside the cell. Reversible modification provides physiological responsiveness to the delivery peptides.
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18 Claims
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1. A conjugate delivery system composition for delivering an RNA interference polynucleotide to a liver cell in vivo comprising:
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RNAi-A and Melittin-(L-Gal)xwherein, Melittin is a melittin peptide, L is physiologically labile reversible linkage wherein cleavage of L-Gal restores an amine on Melittin, Gal is an Asialoglycoprotein Receptor (ASGPr) ligand, x is an integer having a value greater than 80% of primary amines of Melittin, RNAi is an RNA interference polynucleotide, and A is either a hydrophobic group having at least 20 carbon atoms or a galactose cluster. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 16, 17, 18)
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14. The composition of 1 wherein RNAi is linked to A via a physiologically labile linkage L2.
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15. The composition of 14 wherein L2 is orthogonal to L.
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