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Modulators of coagulation factors with enhanced stability

a coagulation factor and pharmacological activity technology, applied in the field of coagulation factor pharmacological activity regulation, can solve the problems of unrealized use of unmodified rna as a therapeutic agent, no available agent meets the therapeutic endpoints of both bioavailability and efficacy, and the major cause of death of adult populations in developed nations. , to achieve the effect of convenient neutralization, improved bioavailability and favorable anticoagulant properties

Inactive Publication Date: 2007-05-10
REGADO BIOSCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The aptamers provide effective anticoagulant properties with controlled pharmacokinetics and duration of action, allowing for precise regulation of coagulation, reducing the risk of bleeding complications and improving therapeutic outcomes during medical interventions.

Problems solved by technology

Despite substantial efforts to treat and prevent thrombotic events, arterial thrombosis continues to be the major cause of death in adult populations of developed nations.
Although numerous medical strategies exist for treating thrombosis, no available agent meets the therapeutic endpoints of both bioavailability and efficacy, while also having a reasonable safety profile (see Feuerstein et al.
Unmodified RNA is not realistically used as a therapeutic agent since blood is rich in ribonucleases.
However, there is no way to predict how a particular modification changes aptamers.
In particular, when additional limitations are required, as is the case with modulatable aptamers, no techniques exist to predict how one or more modifications can affect the capacity of the aptamer to regulate its ligands and at the same time continue to be regulated by antidote binding.

Method used

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  • Modulators of coagulation factors with enhanced stability
  • Modulators of coagulation factors with enhanced stability
  • Modulators of coagulation factors with enhanced stability

Examples

Experimental program
Comparison scheme
Effect test

example 1

Substitution of 2′-O-methyl for 2′-hydroxyl Sugars in Sectors

[0332] 2′-Hydroxyl purines were substituted with 2′-O-methyl purines in the 4 secondary structure units of in which purine residues are present: Stem 1 (Apt 1); Loop 1 (Apt 2); Stem 2 (Apt 3); Loop 2 (Apt 4) (see FIG. 1A).

[0333] Procedure: The anticoagulant activity of AptA derivatives Apt 1-5 was evaluated in standard APTT coagulation assays over compound concentrations ranging from 1 uM to low nanomolar (FIG. 2). The “neutralizability” of Apt1-5 was evaluated in standard APTT antidote assays over AptA antidote concentrations (AptA AD; see sequence listings) ranging from 5 uM and down (FIG. 2). For these assays, the concentration of AptA and derivatives was fixed at 125 nM.

[0334] Apt 4 showed gain of anticoagulant activity (FIG. 2); Apt 1-3 showed moderate loss of activity; and Apt 5 showed severe loss of activity. Apt 1-3 exhibit enhanced neutralization, suggesting that introduction of 2′ -O-methyl residues within the...

example 2

Stem 1 Modifications

[0336] Two “families” of stem 1 variants were designed (Apt 6-8 and 9-11; FIG. 1B) consisting of 4, 5, and 6 basepair stems. All constructs were designed in the Apt-2 background. Stem 1 sequences were evaluated for the ability to design complementary antidote oligonucleotides to them such that the antidotes contain minimal secondary structure, and for the ability of the aptamer to assume the proper secondary structure.

[0337] Stems were wholly 2′-O-methyl modified. Antidote oligonucleotides were designed specific for Apt 6-11 that bind to their respective target aptamer in the same register as AptA AD (see sequence listings below).

[0338] Experiments: The anticoagulant activity of Apt 6-11 was evaluated in standard APTT coagulation assays over compound concentrations ranging from 1 uM to low nanomolar. The antidote control of Apt 6-11 was evaluated in standard APTT antidote assays over antidote concentrations ranging from 5 uM and down. For these assays, the con...

example 3

Stem 1 Sugar Chemistry

[0341] The anticoagulant activity of Apt 12-17 was evaluated in standard APTT coagulation assays over compound concentrations ranging from 1 uM to low nanomolar. The “neutralizability” of Apt 12-17 was evaluated in standard APTT antidote assays over antidote concentrations ranging from 5 uM and down. For Apt 12, 14, 15, and 16, the aptamer concentration was fixed at 125 nM in these assays, and for Apt 13 and 17, the aptamer concentration was fixed at 250 nM.

[0342] Comparison of the anticoagulant activity of Apt 12 with Apt 13 and Apt17 (FIG. 5) demonstrates that the loss of activity observed for Apt6-11 is due to the presence of 2′-O-methyl substitutions at one or more critical residues. Comparison of the anticoagulant activity of Apt14 to Apt12 indicates that the stretch of 4 consecutive guanosines within stem 1 can be altered without a significant impact on anticoagulant activity. Comparison of Apt15 and 16 with Apt 2, 12 and 17 a) demonstrates that the pre...

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Abstract

The invention provides improved nucleic acid ligands with enhanced stability that inhibit coagulation and improved modulators of the nucleic acids to provide ideal modulators of coagulation. These improved nucleic acids and modulators are particularly useful for inhibiting coagulation in a host undergoing a therapeutic regime such as surgery or coronary artery bypass.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application is a continuation-in-part of U.S. application Ser. No. 11 / 113,378, filed Apr. 22, 2005.TECHNICAL FIELD [0002] An improved agent, composition and method to regulate the pharmacological activity of a coagulation factor with nucleic acid ligands (e.g., aptamers) that have improved stability is disclosed. BACKGROUND [0003] Despite substantial efforts to treat and prevent thrombotic events, arterial thrombosis continues to be the major cause of death in adult populations of developed nations. Although numerous medical strategies exist for treating thrombosis, no available agent meets the therapeutic endpoints of both bioavailability and efficacy, while also having a reasonable safety profile (see Feuerstein et al. (1999) Arterioscler. Thromb. Vasc. Biol. 19:2554-2562). [0004] Under normal circumstances, an injury to vascular endothelial cells lining a blood vessel triggers a hemostatic response through a sequence of events c...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K48/00C07H21/02C08G63/91C12N15/115C12Q1/68
CPCA61K31/711A61K47/48215A61K48/00C07H21/02C08G65/329C08L2203/02C12N2310/351C12N15/115C12N2310/321C12N2310/322C12N2310/3521A61K47/60A61P29/00A61P7/02A61P7/04A61P9/00A61P9/10C07K14/003C12N2310/16C12N2310/531
Inventor RUSCONI, CHRISTOPHER P.
Owner REGADO BIOSCI
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