Methods for treating tweak-related conditions

a technology of tweak expression and agent, applied in the direction of peptide/protein ingredients, depsipeptides, fusion polypeptides, etc., can solve the problems of inability to efficiently deliver a death signal and lack of complete understanding of what conditions or diseases are related to tweak expression and function, and achieve the effect of promoting tissue regeneration and replacemen

Inactive Publication Date: 2006-10-26
BIOGEN MA INC
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0017] In other embodiments, the invention relates to methods for identifying TWEAK agonists or antagonists useful as therapeutic agents for the treatment of TWEAK-related conditions. In another embodiment, the invention relates to transgenic animals expressing exogenous DNAs encoding TWEAK polypeptides. A further embodiment of this invention includes the use of TWEAK as a molecular marker for disease.

Problems solved by technology

Lastly, there those members that cannot efficiently deliver a death signal.
Currently, the art lacks a complete understanding of what conditions or diseases are related to TWEAK expression and function, including the role of TWEAK in both inflammatory and non-inflammatory conditions.

Method used

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  • Methods for treating tweak-related conditions
  • Methods for treating tweak-related conditions
  • Methods for treating tweak-related conditions

Examples

Experimental program
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Effect test

example 1

Generation of TWEAK Transgenic Mice

[0159] In order to identify target organ(s) for TWEAK activity and the biological consequences of TWEAK signaling in vivo, two murine TWEAK expression constructs were created and used for the overexpression of TWEAK peptides in normal (C57Bl / 6×DBA / 2)F1 and (C57Bl / 6×SJL / J)F2 mice using standard transgenic techniques. R. S. Williams and P. D. Wagner, J. Applied Physiology 88:1119-1126 (2000). The TWEAK expression constructs used were as follows: (1) A TWEAK cDNA from amino acids 101-249 of SEQ ID NO:1, encoding a soluble form of murine TWEAK (designated sTWEAK) downstream of a murine IgG signal sequence was inserted into the CH269 expression vector (a derivative of vector PCDEP4 (Invitrogen) containing the SV40 poly A addition sequence) downstream of the human alpha1 anti-trypsin (AAT) promoter and a beta-globin intron and upstream of the human growth hormone (hGH) poly A sequence; and (2) A cDNA encoding the full-length, transmembrane form of the p...

example 2

Overexpression of TWEAK in Mice Infected with an Adenoviral Vector Delivering an Exogenous DNA Encoding sTWEAK

[0162] In order to identify the biological effects of overexpression of TWEAK in vivo, 8-10 week old C57BL / 6 female adult mice were infected with a replication-defective adenoviral vector with a cytomegalovirus (CMV) promoter driving the cDNA for either murine sTWEAK (“Adeno-TWEAK”) or jellyfish green fluorescent protein (“GFP”) using standard adenoviral techniques as described in Tao et al., Molecular Therapy 3:28-35 (2001). An adenoviral vector comprising GFP (“Adeno-GFP”) was used as the negative control. To determine whether mice were successfully infected with the Adeno-TWEAK construct, TWEAK protein levels in the serum were determined and monitored at various time points using standard ELISA assays.

[0163] Systemic overexpression of murine sTWEAK in the adult mice induced tissue changes in at least three major organs: liver, kidney and heart. See, Table 1. The phenoty...

example 3

sTWEAK and FL-TWEAK

Induce Dilated Cardiomyopathy

[0164] Four of the surviving PCR+ serum sTWEAK+ founders from Example 1 were sacrificed and examined for gross morphological abnormalities. See, Table 2. Macroscopic observation at the time of necropsy revealed enlarged hearts, some 2-3 fold increased in size as compared to those of normal animals. Since the enlarged heart phenotype was observed in multiple independent sTWEAK transgenic founders, it is highly unlikely to be due to independent insertional events. Furthermore, an analysis of the serum chemistry of the sTWEAK transgenic mice showed elevated cardiac specific creatine kinase.

TABLE 2sTWEAK Transgenic MiceFOUNDERSSERUM TWEAKPHENOTYPE10 PCR+0.06-3.0μg / ml9 / 10 dead at 4-5 months4 / 5 submitted forhistophathologicalexamination had enlargedheart13 PCR+ng / ml1 / 13 dead at 6 monthswith enlarged heart 4 PCR−—0 / 4 dead at 6 months

[0165] The enlarged heart phenotype was also observed in individual mice from one FL-TWEAK transgenic line ...

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Abstract

The present invention provides methods and agents for the treatment of TWEAK-related conditions, including cardiac, liver, kidney, lung, adipose, skeletal, muscle, neuronal, bone and cartilage conditions. The invention also provides methods for identifying TWEAK agonists or antagonists for the treatment of TWEAK-related conditions. Additionally, the invention provides transgenic animals that express an exogenous DNA encoding a TWEAK polypeptide, or fragments, analogs, or muteins thereof, and methods for using such animals to identify TWEAK agonists or antagonists. The invention further provides methods for diagnosing a disease based on TWEAK expression. The invention also provides methods for affecting cellular differentiation of progenitor cells using TWEAK polypeptides, agonists, or antagonists.

Description

TECHNICAL FIELD OF THE INVENTION [0001] The present invention relates to methods and agents for the treatment of TWEAK-related conditions, including cardiac, liver, kidney, lung, adipose, skeletal muscle, neural, bone, cartilage, skin, gastrointestinal, pancreatic, reproductive organ and connective tissue diseases. The invention also relates to methods for identifying TWEAK agonists or antagonists for the treatment of TWEAK-related conditions. Additionally, the invention relates to transgenic animals that express an exogenous DNA encoding a TWEAK polypeptide, or fragments, analogs, or muteins thereof and methods for using such animals to identify TWEAK agonists or antagonists. The invention further relates to methods for diagnosing a disease based on TWEAK expression. The invention also relates to methods for affecting cellular proliferation or differentiation of progenitor cells using TWEAK polypeptides, agonists or antagonists. BACKGROUND OF THE INVENTION [0002] Members of the Tum...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K49/00A61K39/395A61K38/17A01K67/027A61K38/00A61K45/00A61P1/00A61P1/18A61P15/00A61P17/00A61P19/00A61P19/04A61P25/00A61P43/00C07K14/28C07K14/525C07K14/705C07K16/24C07K16/28C07K19/00C12N5/074C12N15/09C12P21/08C12Q1/02C12Q1/68G01N33/15G01N33/50G01N33/53
CPCA01K2217/05A61K38/00A61K2039/505C07K14/70575C07K16/241C07K2319/00C07K2319/30C07K14/525C07K16/22C07K16/2875A61K39/39566A61P1/00A61P1/04A61P1/16A61P1/18A61P11/00A61P13/00A61P13/02A61P13/04A61P13/12A61P15/00A61P15/08A61P17/00A61P19/00A61P19/04A61P21/00A61P25/00A61P29/00A61P3/04A61P43/00A61P9/00A61P9/04A61K39/395A61K39/00A61K38/191A61K39/39533A61K39/3955A61K45/06
Inventor BURKLY, LINDAJAKUBOWSKI, ANIELAZHENG, TIMOTHYHAHM, KYUNGMIN
Owner BIOGEN MA INC
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