Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Patent
1998-04-23
2000-08-01
Elliott, George C.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
424450, 435183, 435194, 435325, 435366, 435371, 435375, 536 231, 536 2431, 536 245, A61K 4800, A61K 9127, C12N 1585, C07H 2104
Patent
active
06096720&
DESCRIPTION:
BRIEF SUMMARY
This invention relates to liposomal oligonucleotide compositions, their preparation and their use.
Alterations in cellular genes which directly or indirectly control cell growth and differentiation are considered to be the main cause of cancer. There are some thirty families of genes, called oncogenes, which are implicated in human tumor formation. Members of one such family, the raf gene family, are frequently found to be mutated in human tumors. The raf family includes three highly conserved genes termed A-, B- and c-raf (also called raf-1). c-Raf, the best characterized member of the raf family, is the cellular homologue of v-raf, the transforming gene of the murine sarcoma virus 3611. Raf genes encode protein kinases that are thought to play important regulatory roles in signal transduction processes that regulate cell proliferation. Mutation of raf genes causing a truncation or other modification that leads to the expression of raf kinase without a functional negative regulatory domain at the amino-terminal end results in conversion to a form which is implicated in transformation of mammalian cells in culture, and tumor formation. A raf gene having an absent or inactive regulatory domain is said to be "activated." Activated (truncated) raf has been detected in a variety of human cancers including small-cell lung carcinoma, primary stomach cancer, renal cancer, breast cancer, laryngeal cancer, skin fibroblasts from members of a cancer-prone family (Li-Fraumeni syndrome), and in a human glioblastoma cell line. Abnormal expression of the normal (non-activated) c-raf protein is believed to play a role in abnormal cell proliferation since it has been reported that 60% of all lung carcinoma cell lines express unusually high levels of normal c-raf mRNA and protein. Rapp et al., The Oncogene Handbook, E. P. Reddy, A. M. Skalka and T. Curran, eds., Elsevier Science Publishers, New York, 1988, pp. 213-253.
Oligonucleotides have been employed as therapeutic moieties in the treatment of disease states in animals and man. For example, there have been identified antisense, triplex and other oligonucleotide compositions which are capable of modulating expression of genes implicated in viral, fungal and metabolic diseases. There remains a need for compositions which can effectively inhibit abnormal raf gene expression, i.e. inhibit expression of the activated raf product or inhibit unusually high level of expression of the normal raf product.
It has now been found that compositions which inhibit abnormal gene expression and retain high anti-hyperproliferative activity after prolonged circulation in the bloodstream can be prepared by formulation of oligonucleotides capable of inhibiting raf expression which are targeted to mRNA encoding human raf within sterically stablised liposomes. These compositions facilitate the reduction of accumulation of oligonucleotide in non-target organs and reduction of acute and chronic side effects during prolonged treatment.
Accordingly, the present invention provides a pharmaceutical composition comprising (A) an oligonucleotide 8 to 50 nucleotides in length, which is targeted to mRNA encoding human raf and is capable of inhibiting raf expression, entrapped in (B) sterically stabilised liposomes.
The relationship between an oligonucleotide and its complementary nucleic acid target to which it hybridises is commonly referred to as "antisense". Targetting an oligonucleotide to a chosen nucleic acid target may involve a multistep process. The process usually begins with identifying a nucleic acid sequence whose function is to be modulated. This may be, as examples, a cellular gene (or mRNA made from the gene) whose expression is associated with a particular disease state, or a foreign nucleic acid from an infectious agent. In the present invention, the target is a nucleic acid encoding raf; in other words, the raf gene or mRNA expressed from the raf gene. The targeting process also includes determination of a site or sites within the nucleic acid sequence for the oligonucleotide interact
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Hamilton Karen Ophelia
Love William Guy
Nicklin Paul Leslie
Phillips Judith Ann
Elliott George C.
McCormack Myra H.
Novartis AG
Nowak Henry P.
Shibuya Mark L.
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