Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Reexamination Certificate
2002-10-16
2004-12-07
Park, Hankyel T. (Department: 1648)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
C435S091100, C435S375000, C435S455000, C514S04400A, C536S023100, C536S024500, C536S025300, C536S031000
Reexamination Certificate
active
06828105
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to antisense oligomers for use in treating a picornavirus, calicivirus, togavirus or flavivirus infection, antiviral treatment methods employing the oligomers, and methods for monitoring binding of antisense oligomers to a viral genome target site.
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BACKGROUND OF THE INVENTION
RNA viruses cause many diseases in wildlife, domestic animals and humans. These viruses are genetically and antigenically diverse, exhibiting broad tissue tropisms and a wide pathogenic potential. The incubation periods of some of the most pathogenic viruses, e.g. the caliciviruses, are very short. Viral replication and expression of virulence factors may overwhelm early defense mechanisms (Xu, 1991) and cause acute and severe symptoms.
There are no specific treatment regimes for many viral infections. The infection may be serotype specific and natural immunity is often brief or absent (Murray et al., 1998). Immunization against these virulent viruses is impractical because of the diverse serotypes. RNA virus replicative processes lack effective genetic repair mechanisms, and current estimates of RNA virus replicative error rates are such that each genomic replication can be expected to produce one to ten errors, thus generating a high number of variants (Hollan, 1993). Often, the serotypes show no cross protection, such that infection with any one serotype does not protect against infection with another. For example, vaccines against the vesivirus genus of the caliciviruses would have to provide protection against over 40 different neutralizing serotypes (Smith et al., 1998a), and vaccines for the other genera of the
Caliciviridae
are expected to have the same limitations.
Antisense agents have been proposed for treating various types of viral infection. In general, the specific proposals to date can be classified according to the type of virus targeted, the viral-genome target, and the type of oligonucleotide backbone employed in the antisense compound. Among the viruses that have been targeted are vesicular stomatitis virus (Robbins and Lebleu, 1999), influenza virus (Mizuta et al., 1999), hepatitis B virus (Wu and Wu, 1992), human papilloma virus (Alvarez-Salas et al., 1999), herpes simplex virus (Aurelian and Smith, 2000), HIV (Kusunoki et al., Wei et al., 2000) and foot-and-mouth disease virus (Gutierrez et al., 1993). Viral genome targets that have been proposed include the IE-2 gene of cytomegalovirus (Green et al., 2000), a stem-loop structure at the 5′ non-coding region, the translation initiation codon, a core protein coding sequence of the hepatitis C virus, and the second functional initiator AUG of the foot-and-mouth disease virus (Hanecak et al., 1996; Alt et al., 1995; Gutierrez et al., 1993). Finally, a wide variety of antisense backbone structures have been proposed, including the negatively charged phosphorothioate (PSO) backbone oligomers, particularly the phosphorothioate oligodeoxynucleotides (Hanecak et al., 1996; Alt et al., 1995; Gutierrez et al., 1993) and uniformly modified 2′-methoxyethoxy phosphodiester oligonucleotide (Hanecak et al., 1996).
Discovery and development generally involves demonstration of antiviral activity in cell culture. A compilation of antiviral experiments in cell culture is provided in Table 1 below.
TABLE 1
In vitro Antiviral Antisense Studies
Virus
Reference
Herpes Simplex
Gao et al. (1989) J. Biol. Chem. 264: 11, 521
Herpes Simplex
Hoke et al. (1991) Nucl. Acids Res. 19: 5743
Herpes Simplex 1
Smith et al. (1986) Proc. Natl. Acad Sci 83: 2787
HIV-tat
Stevenson & Iversen (1989) J. Gen. Virol. 70: 2673
HIV-aptamer
Matsukura et al. (1987) Proc. Natl. Acad Sci 84:
7706
HIV-rev
Matsukura et al. (1989) Proc. Natl. Acad Sci 86:
4244
HIV-gag
Agrawal et al. (1989) Proc. Natl. Acad Sci 86: 7790
HIV-LTR
Vickers et al. (1991) Nucl. Acids Res. 19: 3359
TAR element
VSV
Agris et al. (1986) Biochemistry 25: 6268
VSV-N protein
Lamaitre et al. (1987) Proc. Natl. Acad Sci 84: 1987
HPV-E2
Cowsert et al. (1993) Antimic. Agent Chemo. 37:
HBV surface gene
Goodarzi et al. (1990) J. Gen Virol. 71: 3021
HBV
Wu & Wu (1992) J Biol Chem 267: 12, 436-12, 439
SV40
Graessmann et al. (1991) Nucl. Acids Res. 19: 53
Influenza
Kabanov et al. (1990) FEBS Lett. 259: 327
Influenza
Leiter et al. (1990) Proc. Natl. Acad Sci 87: 3430
Rous Sarcoma Virus
Zamecnik & Stephenson (1978) Proc. Natl.
Acad Sci 75: 280
CMV immed. early
Anderson et al. (1996) Antimic. Agent
RNA
Chemo. 40: 2004
Clinical trials have been initiated for antisense therapeutics targeting HIV, HPV, CMV and HCV (Table 2 below), all using phosphorothioate-linked oligonucleotides. As seen, the clinical trial experience to date indicates some failures, although antisense against CMV infection (ISIS2922) has been approved by the FDA, making this the only antisense agent approved by the FDA to date.
TABLE 2
Clinical Trials with Antisense for Antiviral Therapy
Name
Company
Virus
Status
GEM91
Hybridon
HIV-gag
250 pts. Discont. 1997
ISIS2105
ISIS
HPV (6 & 11)
400 pts. Fail phase III
ISIS2922
ISIS
CMV-IE2
HIV retinitis approved
GEM132
Hybridon
CMV
Phase I
ISIS14803
ISIS
HCV
Phase I
The initial optimism towards antisense approaches to effective antiviral therapeutics has been blunted. Many of the effective antisense strategies employed in cell culture models (e.g. tho
Iversen Patrick L.
Skilling Douglas E.
Smith Alvin W.
Stein David A.
AVI BioPharma Inc.
Dehlinger Peter J.
Gorthey Lee Ann
Park Hankyel T.
Perkins Coie LLP
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