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Polynucleotide agents targeting serpinc1 (AT3) and methods of use thereof

a technology of polynucleotide agents and serpinc1 is applied in the field of polynucleotide agents targeting serpinc1 (at3), which can solve the problems of refractory to replacement coagulation factor, difficult treatment of bleeds in such subjects, and inability to properly control bleeds, etc., to achieve stabilization of hemoglobin levels, decrease in intravascular hemolysis, and decrease in serpinc1 protein levels

Inactive Publication Date: 2020-04-02
GENZYME CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The invention provides a way to prevent symptoms in people with diseases that would benefit from reduced expression of a protein called Serpinc1. This is done by giving them a medication that reduces the levels of the protein. The medication can reduce the amount of damage to the liver, stabilize the levels of a certain protein in the blood, and decrease the levels of another protein in the blood.

Problems solved by technology

Although, at present there is no cure for hemophilia, it can be controlled with regular infusions of the deficient clotting factor, e.g., factor VIII in hemophilia A. However, some hemophiliacs develop antibodies (inhibitors) against the replacement factors given to them and, thus, become refractory to replacement coagulation factor.
Accordingly, bleeds in such subjects cannot be properly controlled.
The development of high-titer inhibitors to, for example, factor VIII and other coagulation factors, is the most serious complication of hemophilia therapy and makes treatment of bleeds very challenging.
Currently, the only strategies to stop bleeds in such subjects are the use of “bypassing agents” such as factor eight inhibitor bypass activity (FEIBA) and activated recombinant factor VII (rFVIIa), plasmapheresis, continuous factor replacement, and immune tolerance therapy, none of which are completely effective.

Method used

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  • Polynucleotide agents targeting serpinc1 (AT3) and methods of use thereof
  • Polynucleotide agents targeting serpinc1 (AT3) and methods of use thereof
  • Polynucleotide agents targeting serpinc1 (AT3) and methods of use thereof

Examples

Experimental program
Comparison scheme
Effect test

example 1

Synthesis

[0484]The antisense polynucleotides targeting Serpinc1 were synthesized using standard synthesis methods well known in the art.

[0485]Design of antisense polynucleotides was carried out using the following transcripts from the NCBI RefSeq collection: Human—NM_000488.2, NM_000488.3; Rhesus—NM_001104583.1; Dog—XM_856414.1; Mouse—NM_080844.4; Rat—NM_001012027.1.

[0486]A detailed list of antisense molecules targeting Serpinc1 is shown in Tables 3 and 4 below.

TABLE 2Abbreviations of nucleotide monomers used in nucleic acid sequence representation. It will be understood that these monomers, when present in an oligonucleotide, are mutually linked by 5'-3'-phosphodiester bonds.AbbreviationNucleotide(s)AAdenosine-3'-phosphateAf2'-fluoroadenosine-3'-phosphateAfs2'-fluoroadenosine-3'-phosphorothioateAsadenosine-3'-phosphorothioatea2'-O-methyladenosine-3'-phosphateas2'-O-methyladenosine-3'-phosphorothioateCcytidine-3'-phosphatedA2{grave over ( )}-deoxyadenosine-3{grave over ( )}-phosphat...

example 2

Screening

[0487]Serpinc1 (AT3) gapmer transfections were done at 5 nM. Single dose screen of 184 Serpinc1 oligos was performed in Huh7 cells, directly after seeding 25,000 cells per well on 96 well plates. Each oligo was transfected in quadruplicate with 0.5 μl Lipofectamine 2000 / well. Transfections were harvested 24 h after seeding / transfection. Transfection of an Aha1-LNA gapmer, and mock transfections were performed quadruplicate on each plate as control. Mean values of Serpinc1 / GAPDH from Aha1-LNA transfection was set as 100% Serpinc1 expression, which is the reference for all other mean values shown in Table 5. At the same time, the Aha1-LNA also served as a transfection control on each plate.

[0488]The complete screen was performed in two transfection “sessions”. Overall, transfection efficiency with Aha1-oligo was between ˜60-70% at 5 nM. All Serpinc1 oligos were less efficient than the Aha1-LNA at the same concentration.

[0489]Transfection efficiency for each plate was determin...

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Abstract

The invention relates to polynucleotide agents targeting the Serpinc1 (AT3) gene, and methods of using such polynucleotide agents to inhibit expression of Serpinc1 and to treat subjects having a bleeding disorder, e.g., a hemophilia.

Description

RELATED APPLICATIONS[0001]This is a continuation application of U.S. patent application Ser. No. 15 / 499,981, filed on Apr. 28, 2017, which is a 35 § U.S.C. 111(a) continuation application which claims the benefit of priority to PCT / US2015 / 057717, filed on Oct. 28, 2015, which claims priority to U.S. Provisional Application No. 62 / 072,686, filed on Oct. 30, 2014. The entire contents of each of the foregoing applications are incorporated herein by reference.SEQUENCE LISTING[0002]The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on May 8, 2019, is named 117811_02503_SL and is 299,735 bytes in size.BACKGROUND OF THE INVENTION[0003]Serpinc1 or antithrombin III (AT3) is a member of the serine proteinase inhibitor (serpin) superfamily Serpinc1 is a plasma protease inhibitor that inhibits thrombin as well as other activated serine proteases of the coagu...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C12N15/113
CPCC12N2310/341C12N2310/351C12N2310/346C12N15/113C12N2310/3231C12N2320/35C12N2310/315C12N2310/11C12N2310/3341C12N2310/321C12N2310/3525C12N2310/3521
Inventor HINKLE, GREGORY
Owner GENZYME CORP
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