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Antisense antiviral compounds and methods for treating a filovirus infection

a technology of antiviral compounds and filovirus, applied in the field of antiviral compounds and methods for treating filovirus infections, can solve the problems of preventing affecting the development of effective ebola virus treatment, and unable to effectively treat an infection by any of these viruses. to achieve the effect of inhibiting replication

Active Publication Date: 2006-12-14
UNITED STATES ARMY U S ARMY MEDICAL RES & MATERIAL COMMAND +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In general, no effective antiviral therapies are available to treat an infection by any of these viruses.
Although they cause only a few hundred deaths worldwide each year, filoviruses are considered a significant world health threat and have many of the characteristics commonly associated with biological weapons since they can be grown in large quantities, can be fairly stable, are highly infectious as an aerosol, and are exceptionally deadly (Borio, Inglesby et al.
The development of an effective therapeutic for Ebola virus has been hindered by a lack of reagents and a clear understanding of filovirus pathogenesis, disparity between animal models, and both the difficulty and danger of working with Ebola virus in biosafety level (BSL)-4 conditions (Geisbert and Hensley 2004; Burnett, Henchal et al.
Host-directed therapeutics alone have not proven to be a sufficiently efficacious therapeutic approach.

Method used

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  • Antisense antiviral compounds and methods for treating a filovirus infection
  • Antisense antiviral compounds and methods for treating a filovirus infection
  • Antisense antiviral compounds and methods for treating a filovirus infection

Examples

Experimental program
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Effect test

example 1

Antiviral Efficacy of Ebola Virus-Specific PMOs in Rodents

[0188] To determine the in vivo efficacy of the Ebola virus-specific PMOs, the survival of mice treated with 500 μg doses of the individual PMOs (VP24-AUG, L′-AUG and VP35′-AUG, SEQ ID NOs:34, 17 and 22, respectively) at 24 and 4 hours before challenge with 1000 plaque-forming units (pfu) of mouse-adapted Ebola virus was determined. The VP35′-AUG, VP24-AUG and L′-AUG PMOs exhibited a wide range of efficacy against lethal EBOV infection and the VP35′-specific PMO provided nearly complete protection (FIG. 11A). Next, we performed a dose response experiment with the VP35 PMO and found that reducing the dose of the PMO from 1,000 to 100 μg reduced the efficacy substantially (FIG. 11B). Hence, to further enhance efficacy, we decided to use a combination of all three PMOs. This combination of PMOs administered 24 and 4 h before lethal Ebola virus challenge resulted in robust protection and showed substantial enhancement in protect...

example 2

Antiviral Efficacy of Ebola Virus-Specific PMOs in Non-Human Primates

[0191] Based on the encouraging results both in vitro and in rodents, a trial in nonhuman primates was performed. Four rhesus monkeys were treated with PMO from two days prior to Ebola virus infection through day 9 of the infection. The naïve control monkey in this experiment received no treatment and succumbed to Ebola virus infection on day 10 as shown in FIG. 15A. Of 12 rhesus monkeys that have been infected in the inventors' laboratory with the same seed stock of virus, all died of Ebola virus between days 7 and 10 as shown in FIG. 15A. One of the PMO-treated monkeys succumbed to the infection on day 10. A second PMO-treated monkey cleared the EBOV infection from its circulation between days 9 and 14, but was unable to recover from disease and died on day 16 as shown in FIGS. 15A and 15B. The two surviving monkeys had no symptoms of disease beyond mild depression until day 35, at which time they were euthanize...

example 3

Increased Antisense of Activity using PMO with Cationic Linkages

[0193] Two PMOs were synthesized using cationic linkages for a subset of the oligomer linkages as shown in Sequence Listing for SEQ ID NOs:40 and 41. These oligomers incorporated the cationic linkage (1-piperazino phosphoramidate) shown in FIG. 2H at the positions indicated with a “+”. These two PMOs target the EBOV VP24 mRNA. A cell free translation assay was performed using the VP24:luciferase mRNA as the input RNA. PMO with and without cationic linkages were compared for their ability to inhibit luciferase expression and the results are shown in FIG. 16. Compared to the uncharged PMO with the same base sequence, the PMOs with between 6 and 8 cationic linkages demonstrated between 10 and 100-fold increased antisense activity in this assay.

[0194] Based on the experiments performed in support of the invention as described above in the Examples, efficacious anti-filovirus PMOs have been identified. The antiviral PMOs d...

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Abstract

The invention provides antisense antiviral compounds and methods of their use and production in inhibition of growth of viruses of the Filoviridae family, and in the treatment of a viral infection. The compounds and methods relate to the treatment of viral infections in mammals including primates by Ebola and Marburg viruses. The antisense antiviral compounds are morpholino oligonucleotides having: a) a nuclease resistant backbone, b) 15-40 nucleotide bases, and c) a targeting sequence of at least 15 bases in length that hybridizes to a target region selected from the following: i) the AUG start site region of VP35, as exemplified by SEQ ID NOS:67-71 or ii) the AUG start site region of VP24, as exemplified by SEQ ID NOS:72-76.

Description

[0001] This is a continuation-in-part of U.S. patent application Ser. No. 11 / 264,444, filed Oct. 31, 2005, which claims the benefit of priority to U.S. provisional Patent Application No. 60 / 671,694 filed Apr. 14, 2005, and U.S. provisional Patent Application No. 60 / 624,277 filed Nov. 1, 2004. Both applications are incorporated herein by reference.FIELD OF THE INVENTION [0002] This invention relates to antisense oligonucleotide compounds for use in treating an infection by a virus of the Filoviridae family and antiviral treatment methods employing the compounds. More specifically, it relates to treatment methods and compounds for treating viral infections in mammals including primates by Ebola and Marburg viruses. REFERENCES [0003] Agrawal, S., S. H. Mayrand, et al. (1990). “Site-specific excision from RNA by RNase H and mixed-phosphate-backbone oligodeoxynucleotides.”Proc Natl Acad Sci USA 87(4): 1401-5. [0004] Arora, V. and P. L. Iversen (2001). “Redirection of drug metabolism usin...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K48/00C07H21/02C07F9/6533
CPCC12N15/1131C12N2310/11C12N2310/3513C12N2310/32C12N2310/31A61P31/14
Inventor STEIN, DAVIDIVERSEN, PATRICKBAVARI, SINAWELLER, DWIGHT
Owner UNITED STATES ARMY U S ARMY MEDICAL RES & MATERIAL COMMAND
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