Title:  Oligonucleotide therapies for modulating the effects of herpesviruses

United States Patent:  6,310,044

Assignee:  Isis Pharmaceuticals, Inc. (Carlsbad, CA)

Filed:  April 28, 1992

PCT NO:  PCT/US91/01327

102(e) Date:  April 28, 1992

PCT PUB. Date:  September 5, 1991

Compositions and methods are provided for the treatment and diagnosis of herpesvirus infections. In accordance with preferred embodiments, oligonucleotides are provided which are specifically hybridizable with RNA or DNA deriving from a gene corresponding to one of the open reading frames UL5, UL8, UL9, UL13, UL29, UL30, UL39, UL40, UL42 AND UL52 of herpes simplex virus type 1. The oligonucleotide comprises nucleotide units sufficient in identity and number to effect said specific hybridization. In other preferred embodiments, the oligonucleotides are specifically hybridizable with a translation initiation site; it is also preferred that they comprise the sequence CAT. Methods of treating animals suspected of being infected with herpesvirus comprising contacting the animal with an oligonucleotide specifically hybridizable with RNA or DNA deriving from one of the foregoing genes of the herpesvirus are disclosed. Methods for treatment of infections caused by herpes simplex virus type 1, herpes simplex virus type 2, cytomegalovirus, human herpes virus 6, Epstein Barr virus or varicella zoster virus are disclosed.

SUMMARY OF THE INVENTION

In accordance with the present invention, oligonucleotides and oligonucleotide analogs are provided which are specifically hybridizable with RNA or DNA deriving from a gene corresponding to one of the open reading frames UL5, UL8, UL9, UL13, UL29, UL30, UL39, UL40, UL42 AND UL52 of herpes simplex virus type 1. The oligonucleotide comprises nucleotide units sufficient in identity and number to effect such specific hybridization. It is preferred that the oligonucleotides or oligonucleotide analogs be specifically hybridizable with a translation initiation site and preferably that the oligonucleotide comprise a sequence CAT.

In accordance with preferred embodiments, the oligonucleotides and oligonucleotide analogs are designed to be specifically hybridizable with DNA or even more preferably, RNA from one of the species herpes simplex virus type 1 (HSV-1), herpes simplex virus type 2 (HSV-2), cytomegalovirus, human herpes virus 6, Epstein Barr virus (EBV) or varicella zoster virus (VZV). Such oligonucleotides and analogs are conveniently and desirably presented in a pharmaceutically acceptable carrier.

In accordance with other preferred embodiments, the oligonucleotides and oligonucleotide analogs are formulated such that at least some of the linking groups between nucleotide units of the oligonucleotide units comprise sulfur-containing species such as phosphorothioate moieties.

Other aspects of the invention are directed to methods for diagnostics and therapeutics of animals, especially humans, suspected of having a herpesvirus infection. Such methods comprise contacting either the animal or a body fluid of the animal with oligonucleotides or oligonucleotide analogs in accordance with the invention in order to inhibit the proliferation or effect of such infection, or to effect a diagnosis thereof

Persons of ordinary skill in the art will recognize that the particular open reading frames described for herpes simplex virus type 1 find counterparts in the other viruses named. Thus each of herpes simplex virus type 2, cytomegalovirus, human herpes virus type 6, Epstein Barr virus and varicella zoster virus are believed to have many analogous open reading frames which code for proteins having similar functions. Accordingly, the present invention is directed to antisense oligonucleotide therapy where the oligonucleotides or oligonucleotide analogs are directed to any of the foregoing viruses, or indeed to any similar viruses which may become known hereafter, which have one or more of such analogous open reading frames. For convenience in connection with the present invention, all such viruses are denominated as herpesviruses.

Claim 1 of 9 Claims

What is claimed is:

1. A phosphorothioate or methylphosphonate oligonucleotide analog which comprises 15-50 bases, contains a sequence CAT and is capable of inhibiting activity of a herpesvirus, said oligonucleotide analog being complementary to a translation initiation portion of mRNA from a herpesvirus open reading frame selected from the group consisting of UL5, UL8, UL9, UL13, UL30, UL39, UL40, UL42 and UL52.

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