Anti sense oligonucleotides for blocking IgE receptor synthesis

Details Anti sense oligonucleotides for blocking IgE receptor synthesis Anti sense oligonucleotides for blocking IgE receptor synthesis

1997-11-20

1999-04-06

Elliott, George C.

Organic compounds -- part of the class 532-570 series

Organic compounds

Carbohydrates or derivatives

536 241, 536 243, 536 2431, 536 2433, 435 6, 514 44, C07H 2104, A61K 4800

Patent

active

058920234

DESCRIPTION:

BRIEF SUMMARY
The present invention concerns antisense oligonucleotides which selectively hybridize with one or more genes necessary in blocking the synthesis of the IgE receptor, pharmaceutical compounds comprising them, and their use as IgE inhibitors.
The hypersensitivity of IgE is at least one of the major components exerting a mediating effect in the manifestation of the early and late phases of type I allergic reactions. The physiopathological mechanism may be broken down into the following phases:
Mastocytes and basophils are not the only target cells activated by IgE and intervening in the hypersensitivity reaction. The other effector cells are comprised of epithelial and endothelial cells and other inflammatory cells.
The hypersensitivity reaction is triggered when IgE, produced in excess by B lymphocytes, enters into interaction with the specific receptors on the effector cells.
Two types of receptors have been characterized: one high affinity receptor called the Fc.sub..epsilon. R.sub.I receptor, or type I receptor, and a weak affinity receptor called the Fc.sub..epsilon. R.sub.II receptor, or type II receptor. In addition to the cells intervening in the inflammatory response, these receptors are expressed equally by the sub-population in B and T lymphocytes. The expression of type I receptors or Fc.sub..epsilon. R.sub.I is necessary to unleash the hypersensitivity reaction.
One therapeutic approach to the treatment of allergic reactions consists of blocking the synthesis of IgE or the IgE receptors.
The antisense strategy is a new therapeutic approach intended to obtain the selective modulation of gene expression by an highly selective association with a nucleotide chain (oligonucleotide) with its supplementary sequence on the RNA or DNA messengers or pre-messengers and, consequently, inhibiting the synthesis of the corresponding proteins.
Oligonucleotides complementary to the transcriptional products arc called "antisense" oligonucleotides. The oligonucleotides having the same sequence as the transcriptional products are named "sense" oligonucleotides. Initially these compounds were logically destined to inhibit the formation of a gene product by the suppression of the corresponding RNA messenger, via the mechanism of hydrolytic catilization by the RNAase H. It soon became apparent that the action mechanism of these antisense oligonucleotides was not this simple. These oligonucleotides can interact with a certain number of target cells not containing nucleic acid. These oligonucleotides can interact with the gene, to form triple-helices structures and can inhibit the formation of transcriptional products. Oligonucleotides can interact with the intron-exon junctions of the RNA pre-messenger, thus interfering with the correct splicing of the transcriptional product. Oligonucleotides can hybridize with the messenger RNA in the cytoplasm, by forming an RNA-DNA complex, which is rapidly digested by the enzyme RNAase H, or by preventing the ribosome complex from sliding along the messenger RNA hence blocking its transduction.
Oligonucleotides and, more particularly, modified oligonucleotides, can interact with a number of cellular products such as proteins. These interactions may be sequence specific (for example: transcription factors) or non-sequence specific (for example: growth factors).
Oligonucleotides are often used as a probe, for example for the identification of a complementary strand of the studied oligonucleotide, from an experimental point of view, in pharmacological experiments. For instance, in the domain of IgE, oligonucleotides were used, for example, to prominently display the subunit of the IgE receptor (Proceedings of the National Academy of Sciences of USA, Vol. 85, No. 15, August 1988, pp. 5639-5643). But in this domain, none of the oligonucleotides were used for therapeutic purposes.
The invention concerns the antisense oligonucleotides that selectively hybridize with one or more of the genes necessary to block the synthesis of the IgE receptor.
This invention concerns more particularly the

REFERENCES:
Uhlman et al. "Antisense Oligonucleotides: A New Therapeutic Principle." Chemical Reviews vol. 90 No. 4:544-584, Jun. 1990.
Agrawal, S., "Antisense Oligonucleotides: Towards Clinical Trials" Tibtech vol. 14 376-387, 1996.
Branch, A. "A Good Antisense Molecule is Hard to Find". Tibs vol. 23:45-50, Feb. 1998.
Fournier et al, "Role . . . Proliferation", Blood, vol. 84, No. 6 (1994) pp. 1881-1886.
Zon, "Oligonucleotide . . . Agents", Pharmaceutical Research, vol. 5, No. 9 (1988) pp. 539-549.
Bhatti et al, "Inhibition . . . Epsilon R II", Cell Immunol. 144 (1) (1992) pp. 117-130.
Liu et al, "CDNA . . . Receptor", Proceedings of the National Academy of Sciences of USA, vol. 85, No. 15, pp. 5639-5643.

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