Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Patent
1998-04-06
2000-10-31
Yucel, Remy
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
536 231, 536 241, 435 6, 435455, C07H 2104, C07H 2102
Patent
active
061404926
DESCRIPTION:
BRIEF SUMMARY
This invention relates to an antisense transcript expressed in normal and leukemic B lymphocytes and to synthetic oligodeoxynucleotides (ODN) useful to inhibit the activity of said antisense transcript, thus causing the increased synthesis of immunoglobulins and the death of tumoral cells.
More particularly, this invention relates to an endogenous antisense transcript that complements the pre-mRNA (immature RNA) of the gene coding for the heavy chain of immunoglobulins (IgH), thus exerting a negative control action on the immunoglobulins production.
It is well known that the synthetic oligodeoxynucleotides are short single strand DNA chains. The nucleotide sequence is ordered in a specular fashion to complement the correspondent nucleotide sequence within the mRNA to be inhibited. By that modality they are capable of regulating gene expression in a specific way.
It is important that the oligodeoxynucleotides have a length suitable to optimally hybridize the target mRNA. In general, the minimum length is of 10 and the maximum length is of 100 bases. Preferably, 15-30 bases is the most used length; most preferably the length is of 18 bases since statistical analysis teaches that each sequence of such a length is unique in the human genome.
The oligodeoxynucleotides can act at different steps of the mRNA metabolic pathway, either at nuclear or at cytoplasmic level. It is moreover likely that oligodeoxynucleotides might act at the ribosome level, or straight at the DNA level both in the nucleus and in the mitochondria. The nucleotide length of oligodeoxynucleotides may be selected also in view of the basic knowledge of the person skilled in the art concerning the efficiency in crossing the cellular membranes (Locke S. L. et al.: Mechanism of oligonucleotide uptake by cells: involvement of specific receptors? Proc. Natl. Acad. Sci. USA 86:3474, 1989. Yakubov L. A. et al.: Characterization of oligonucleotide transport into living cells. Proc. Natl. Acad. Sci. USA 86:6454, 1989).
It is also known that discrete regions within specific genes may be transcribed in both directions. More commonly, a single strand (positive) from the double strand is transcribed into mRNA and afterwards translated into protein. In some circumstances, however, the negative strand may also be transcribed (endogenous antisense RNA), playing a regulatory role in the functions of the regular transcript. The antisense transcripts may regulate the synthesis, maturation, stability and translation of the messenger RNA (Green P. J. et al.: The role of antisense RNA in gene regulation. Ann. Rev. Biochem. 55:569, 1990; Krystal G. W. et al.: N-myc mRNA forms RNA-RNA duplex with endogenous antisense transcripts. Mol. Cell Biol. 10:4180, 1990; Taylor E. R. et al.: identification of antisense transcripts of the chicken insulin-like growth factor-lI gene. J. Mol. Endocrinol. 7:145, 1991).
Finally, it is known that the locus coding for the heavy chain of the immunoglobulins (IgH) is composed of sub-loci which undergo an ordered rearrangement during the lymphocyte maturation originating the mature IgH gene. It includes the V region (variable), the D region (diversity), the J region (joining). The above gene segments code for the variable region of the heavy chain of the immunoglobulins and, in the course of the rearrangement, they may loose nucleotides at the extremities of the junction and/or addition of random nucleotides that originate new nucleotide sequences, called N regions, that contribute for the hyper-variation regions of the antibodies.
Upstream to each V segment is located a promoter that is activated upon the segment is rearranged. The promoter is under the influence of the Enhancer sequence (E) located between the J segment and the constant (C) region (FIG. 1).
The sequence of the IgH gene has been already reported in the literature and it is known that the breaking points of the IgH locus are mainly located within the J region (Ravetch J. V. et al.: Structure of the human immunoglobulin locus: characterization of embryonic and rearranged J
REFERENCES:
M. Neurath et al., "The Murine Ig 3'.alpha.Enhancer is a Target Site with Repressor Function for the B Cell Lineage-Specific Transcription Factor BSAP (NF-HB, S.alpha.-BP)", Journal of Immunology, 153 (2) :730-742 (1994).
T. Tanaka et al., "An Antisense Oligonucleotide Complementary to a Sequence in I 2b.gamma.Increases .gamma.2b Germline Transcripts, Stimulates B Cell DNA Synthesis and Inhibits Immunoglobulin Secretion", J. Exp. Med., 175 (2) :597-607 (1992).
Branch et al. "A Good Antisense Molecule is Hard to Find" TIBS vol. 23:45-50, Feb. 1998.
Agrawal S. "Antisense Oligonucleotides: Towards Clinical Trials" TIBTECH vol. 14:376-387, Oct. 1996.
Morelli Susanna
Nicolin Angelo
Quattrone Alessandro
Consiglio Nazionale delle Richerche
McGarry Sean
Yucel Remy
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