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Splice switching oligomers for tnf superfamily receptors and their use in treatment of disease

An oligomer, receptor technology, applied in the field of TNFR protein variants, can solve the problem of not teaching or providing the enlightenment of CD40 splicing element or region, not teaching or providing etc.

Active Publication Date: 2010-11-17
SANTARIS PHARMA AS +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] US2005 / 202531 teaches that antisense oligonucleotides can be used to alter the alternative splicing pattern of CD40, but it does not teach or provide any indication as to which splicing elements or regions of CD40 should be targeted by SSOs, nor does it teach or provide any insight as to which sequence should be used

Method used

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  • Splice switching oligomers for tnf superfamily receptors and their use in treatment of disease
  • Splice switching oligomers for tnf superfamily receptors and their use in treatment of disease
  • Splice switching oligomers for tnf superfamily receptors and their use in treatment of disease

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Embodiment approach

[0472] The present invention provides a method of treating an inflammatory disease or condition comprising administering to a subject one or more splice switch oligomers (SSOs) in an amount that reduces tumor necrosis factor receptor (TNFR) superfamily The amount of ligand activity wherein said one or more SSOs are capable of altering the splicing of pre-messenger RNA encoding said receptor, thereby increasing the production of a stably secreted ligand-bound form of said receptor.

[0473] In one embodiment, the mammalian receptor is selected from the group consisting of TNFRSF1A, TNFRSF1B, TNFRSF3, TNFRSF5, TNFRSF8 and TNFRSFI1A.

[0474] In one embodiment, the receptor is human TNFRSF1A or human TNFRSF1B. In one embodiment, the receptor is human TNFRSF1B.

[0475] In one embodiment, the ligand is TNF-α., RANKL, CD40L LT-α. or LT-β.

[0476] In one embodiment, the disease or condition is selected from the group consisting of rheumatoid arthritis, juvenile rheumatoid arthrit...

Embodiment 1

[0526] Oligonucleotides. Table 6 lists the chimeric locked nucleic acids with alternating 2'deoxy- and 2'O-4'-(methylene)-bicyclic-ribonucleoside phosphorothioates and sequences as described above ( LNA) SSOs. These sequences were synthesized by Santaris Pharma in Denmark. For each SSO, the 5'-terminal nucleoside is 2'oxy-4'-methylene-ribonucleoside and the 3'-terminal nucleoside is 2'deoxyribonucleoside. Table 7 shows compounds with alternating 2'-oxo-methyl-ribonucleoside-phosphorothioate (2'-OMe) and 2'O-4'-(methylene)-bicyclic-ribonucleoside thio Sequences of chimeric LNA SSOs of phosphoesters. These sequences were synthesized by Santaris Pharma in Denmark. LNA is shown in uppercase letters, 2'-OME is shown in lowercase letters.

[0527] Cell culture and transfection. L929 cells were maintained in minimal essential medium (37°C, 5% CO2) supplemented with 10% fetal bovine serum and antibiotics. For transfection, L929 cells were seeded into 24-well plates at 10 5 cel...

Embodiment 2

[0542] Example 2-SSO Splicing Switching Activity on TNFR mRNA

[0543] Table 6 shows the splice switch activity of SSOs having sequences as described in US Application No. 11 / 595,485 and targeting mouse and human TNFRs. At least eight of the SSOs targeting exon 7 of mouse TNFR2 produced some muTNFR2Δ7 mRNA. In particular, SSO 3312 and 3305 induced exon 7 deletions of at least 50%; SSO 3305 treatment resulted in almost complete deletions. Transfection into primary human hepatocytes and at least 7 of the SSOs targeting exon 7 of human TNFR2 produced some huTNFR2Δ7 mRNA. In particular, SSOs 3378, 3379, 3384 and 3459 induced exon 7 deletions in at least 75% ( Figure 2B ), huTNFR2Δ7 was significantly induced into the extracellular medium ( Figure 2A ).

[0544] Table 6: Splice transition activity of SSO

[0545]

[0546] Table 7 contains compounds with alternating 2'-oxy-methyl-ribonucleoside-phosphorothioate (2'-OMe) and 2'-oxo-4'-(methylene)-bicyclic-ribonucleoside thio ...

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Abstract

The present invention relates to splice switching oligonucleotides or splice switching oligomers (SSOs). The preferred SSOs according to the invention target exon 7 of TNFRl (TNFRSFlA) or TNFR2 (TNFRSFlA) pre-mRNA, typically resulting in the production of TNFR variants which comprise a deletion in part or the entire exon 7 respectfully. SSOs targeting exon 7 are found to result in a soluble form of the TNFR, which has thereputic benefit for treatment of inflammatory diseases. The SSO's are characterized in that they are substantially incapable or incapable of recruiting RNaseH.

Description

[0001] This application claims priority to US 60 / 862,350, PCT / US2006 / 043651 and US 11 / 595,485, which are hereby incorporated by reference in their entirety. technical field [0002] The present invention relates to compositions and methods for producing in vivo or in vitro splice variants of the TNFα receptor (TNFR), and the resulting TNFR protein variants. Such variants can be prepared using splice switching oligonucleotides or splice switching oligomers (SSOs) to control the splicing of pre-messenger RNA molecules and regulate protein expression. Preferred SSOs according to the invention target exon 7 or 8 of the TNFR1 (TNFRSF1A) or TNFR2 (TNFRSF1A) pre-messenger RNA (pre-mRNA), typically resulting in a gene comprising part or all of exon 7 or 8, respectively. Deleted TNFR variant. SSOs targeting exon 7 were found to generate a therapeutically useful soluble form of TNFR for the treatment of inflammatory diseases. SSOs are characterized in that they are substantially unabl...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12N15/11A61K31/713C07H21/00A61K48/00C12N15/113
CPCC12N2310/346C07H21/04C12N2310/321C12N15/1138C12N2310/3231C12N2310/315C12N15/111C12N2320/33C12N2310/11A61P29/00A61P43/00C12N2310/3521A61K48/00C07K14/7151C12N15/113
Inventor 亨里克·奥鲁姆彼得·L·萨扎尼
Owner SANTARIS PHARMA AS
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