Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Patent
1992-11-19
1997-01-07
Zitomer, Stephanie W.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
536 245, A61K 3170, G07H 2104
Patent
active
055917208
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
This invention relates to the design and synthesis of antisense oligonucleotides which can be administered to inhibit the replication of cytomegalovirus and treat cytomegalovirus infections. These compounds can be used either prophylactically or therapeutically to reduce the severity of disease caused by cytomegaloviruses. Oligonucleotides and oligonucleotide analogs which are specifically hybridizable with RNA targets are described.
BACKGROUND OF THE INVENTION
Cytomegaloviruses (CMV's) are ubiquitous in nature and are the most common causes of intrauterine infection. Congenital infection is common in newborns of infected mothers. In some populations, as much as 10% of children display perinatal infections. In a small percentage of newborns, the infection is virulent, involving multiple organs. Pronounced involvement of the reticuloendothelial and central nervous system is typical; and the infection is a major cause of mental retardation. Careful testing demonstrates that as many as 50% of severely, prenatally infected adults may display neuropsychiatric disease or deafness. Although extraneural organs are usually spared chronic morbidity, the virus can be detected in the kidney for years.
In the adult, cytomegalovirus-induced mononucleosis is a lingering illness that causes significant morbidity. If it occurs in immunosuppressed patients, the disease is more severe, and it may be complicated by other infectious pathogens which may be fatal. Cytomegalovirus retinitis is a severe problem in immunosuppressed patients that often leads to blindness. Immunosuppressed patients are also very susceptible to CMV pneumonitis, which is one of the most lethal of human viral diseases. Although cytomegalovirus may play a role in the progression of HIV infection to AIDS by stimulating the transcription of the HIV long terminal repeats (LTR) in non-transformed co-infected T cells, histologic examination of adrenals and brains from AIDS patients has suggested that the adrenalitis, encephalitis and peripheral neuropathy were caused by CMV infection.
CMV is considered to be an oncogenic virus. In vitro, CMV can transform cells and stimulate growth. Both human and non-human cells can undergo transformation when incubated with CMV. Transformed cells contain CMV antigens that are oncogenic when inoculated into appropriate animals. Moreover, oncogenic potential has been associated with specific segments of the CMV genome.
Human CMV is a large, enveloped herpesvirus whose genome consists of a double-stranded DNA molecule which is approximately 240,000 nucleotides in length. This genome is the most complex of all DNA viruses and is approximately 50% larger than the genome of herpes simplex virus (HSV). Intact viral DNA is composed of contiguous long (L) and short (S) segments, each of which contains regions of unique DNA sequence flanked by homologous regions of repetitive sequence. As a group, the human CMV isolates share at least 80% sequence homology, making it nearly impossible to classify cytomegaloviruses into subgroups or subtypes, although variations in the restriction endonuclease patterns of various CMV DNA preparations are identifiable in epidemiologically unrelated strains. The DNA of the prototypic strain of CMV (AD 169) has been sequenced and reported to contain a conservative estimate of 175 unique translational open reading frames (ORFs). A number of the predicted CMV gene products show homology to other human herpesvirus gene products. At least 42 ORFs encode putative glycoproteins and several of the CMV ORFs putatively encode proteins with amino acid homology to human opsin receptor proteins.
In permissive human fibroblasts, CMV gene expression is regulated by a cascade of genetic events that act at both the transcriptional and translational levels. CMV gene expression can be divided into three phases which resemble those of HSV defined as the immediate early (IE), early and late periods. Following adsorption, penetration and uncoating of the virus, a group of viral transcripts, immedia
REFERENCES:
Stein et al., Science 261:1004-1012 (20 Aug. 1993).
Cranage et al., Identification and expression of a human CMV glycoprotein with homology to the EBV BXLF2 product . . . , J. Virology 62(4):1416-1422 (Apr. '88).
Kouzarides et al., Sequence and transcription analysis of the human CMV DNA polymerase gene, J. Virology 61(1):125-133 (Jan. '87).
Ratner, Can the antisense message be delivered?, Biotechnology 7:207 (Mar. '89).
Spacte et al., Human CMV strain Towne glycoprotein B is processed by proteolytic cleavage, Virology 167:207-225 (1988).
Stenberg et al., Structural analysis of the major immediate early gene of human CMV, J. Virology 49(1):190-199 (Jan. '84).
Stenberg et al., Multiple spliced and unspliced transcripts from human CMV immediate-early region 2 . . . , J. Virology 56(3):665-675 (Dec. '85).
Zon, Oligonucleotide analogues as potential chemotherapeutic agents, Pharm. Res. 5(9):539-549.
Cohen in Oligonucleotides: Antisense Inhibitors of Gene Expression, CRC Press, Boca Raton, Florida 1989.
P. S. Miller et al., A new approach to chemotherapy based on molecular biology and nucleic acid chemistry: Matagen (masking tape for gene expression), Anti-Cancer Drug Design, vol. 2, pp. 117-129 1987.
Rothenberg, et al., Oligodoexynucleotides as Anti-Sense Inhibitors of Gene Express: Therapeutic Implications, J. Natl. Cancer Inst., 81:1539-1544 1989.
Anderson Kevin P.
Draper Kenneth G.
ISIS Pharmaceuticals Inc.
Zitomer Stephanie W.
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