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Protein carrier system for therapeutic oligonucleotides

An oligonucleotide, therapeutic technology, applied in the field of therapeutic oligonucleotides, can solve the problems of low intracellular delivery efficiency, immune system stimulation, unsatisfactory half-life, etc.

Inactive Publication Date: 2005-07-27
成都海圻生物科技有限公司 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, such a half-life is still unsatisfactory from a therapeutic point of view
[0005] The second problem is the low efficiency of intracellular delivery of ASO to target mRNA
[0006] A third concern is that ASO stimulates the immune system, which can lead to treatment complications
A limitation found in ribozymes as therapeutic agents is their susceptibility to degradation by RNases

Method used

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  • Protein carrier system for therapeutic oligonucleotides
  • Protein carrier system for therapeutic oligonucleotides

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Experimental program
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Embodiment 1

[0155] Embodiment 1: antisense oligonucleotide synthesis

[0156] Specific antisense oligonucleotides MB003 and MB006 were synthesized with a phosphorothioate backbone by Trilink Biotechnology (San Diego, CA). ASO MB003 and MB006 target the mRNA transcript of the human bcl-xl gene (see Simoes-Wust et al., Int. J. Cancer, 87:582-590, 2000; US Patent No. 6,214,986). Overexpression of the human bcl-xl gene has been found to be associated with many cancer cells. Therefore, treatment with an ASO specific for the human bcl-xl gene should reduce or eliminate the proliferation or growth of a variety of cancer cells. The serials of the MB003 and MB006 ASOs are listed below:

[0157] MB-003: 5'-AAAGTATCCCAGCCGCCGTT-3' (SEQ ID NO: 21)

[0158] MB-006: 5'-TCCCGGTTGCTCTGAGACAT-3' (SEQ ID NO: 22)

[0159] Additionally, synthesized as figure 1 Two ASOs containing a 5'-(BMPS)(C6NH) linker and a maleimide reactive group are shown. These two ASOs, designated MB-003M and MB-006M, have a 5'...

Embodiment 2

[0170] Example 2: siRNA conjugates of the invention

[0171] Therapeutic oligonucleotides of the invention composed of modified siRNAs with reactive groups were synthesized. First, the "sense" strand of the duplex RNA is synthesized using known techniques. Add N3_9S-MPA linker at the 3′ end ( figure 2 ) to synthesize the "sense" strand. The synthetic strands with linkers are recovered and purified. The other RNA strand complementary to the sense strand is synthesized, recovered, and purified using known techniques.

[0172] After purification, the "sense" RNA strand is annealed together with the complementary RNA strand to generate siRNA duplex molecules. After annealing, any other purification steps deemed necessary are performed.

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Abstract

Therapeutic oligonucleotides, including antisense oligonucleotides and siRNA, are modified with reactive chemical groups linked by flexible linker molecules. Modified oligonucleotides are capable of forming covalent bonds with mobile proteins, particularly human serum albumin. The resulting complexes possess enhanced cell entry, significantly increased serum half-life, and reduced immune system stimulation, while retaining biological activity, compared to unmodified oligonucleotides. Modified oligonucleotides overcome many of the problems associated with current antisense drugs. A modified oligonucleotide of the invention is administered as a therapeutic agent and hybridizes to a complementary sequence within the targeted RNA molecule.

Description

field of invention [0001] The present invention relates to modified therapeutic oligonucleotides, including antisense oligonucleotides (hereinafter referred to as "ASOs"), ribozymes, which exhibit enhanced cell entry and prolonged therapeutic half-life upon formation of covalent bonds with mobile proteins. , and small interfering RNA (hereinafter referred to as "siRNA"). More specifically, the present invention relates to therapeutic oligonucleotides modified with chemically reactive groups capable of forming specific covalent linkages to human mobile proteins in vivo or ex vivo. In addition, the invention provides methods of introducing therapeutic oligonucleotides into cells, and methods of using them to treat disease conditions. Background of the invention [0002] therapeutic oligonucleotide [0003] Therapeutic oligonucleotides, such as ASOs and siRNAs, are short pieces of single- or double-stranded DNA or RNA designed to hybridize to specific sequences on target DNA ...

Claims

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Application Information

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IPC IPC(8): A61K47/48C07H21/00C12N15/11C12N15/113
CPCA61K47/48284C12N15/1135C12N2310/3513C12N2310/14C12N2310/53C07H21/00C12N15/111C12N2310/315C12N2320/51C12N2310/11A61K47/643
Inventor 谢东
Owner 成都海圻生物科技有限公司
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