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Treatment of acute myocardial infarction (AMI) using encapsulated cells encoding and secreting GLP-1 peptides or analogs thereof

A technology of acute myocardial infarction, GLP-1, applied in this field, can solve the problem of not being able to provide, not having an immune response, not being able to obtain AMI or MI treatment, etc.

Inactive Publication Date: 2011-08-10
BIOCOMPATIBLES UK LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0030] In summary, effective AMI or MI treatments that would allow effective treatment immediately after a myocardial infarction in the patient to be treated are not currently available in the art
In other words, the prior art fails to provide a treatment that reflects the full range of known beneficial effects of GLP-1, such as GLP-1 activity, which strongly reduces damage and possible death of cardiac tissue caused by ischemia or hypoxia without requiring Repeated administration of GLP-1 peptides, and / or without risk of undesired immune response against, e.g. implanted, GLP-1 expressing allogeneic cells

Method used

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  • Treatment of acute myocardial infarction (AMI) using encapsulated cells encoding and secreting GLP-1 peptides or analogs thereof
  • Treatment of acute myocardial infarction (AMI) using encapsulated cells encoding and secreting GLP-1 peptides or analogs thereof
  • Treatment of acute myocardial infarction (AMI) using encapsulated cells encoding and secreting GLP-1 peptides or analogs thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0231] Preparation of genetic constructs

[0232] The coding sequence of GLP-1(7-37) cDNA was synthesized synthetically, such as figure 1 Shown in a, which in turn includes HincII and EcoR1 sites. synthesized separately figure 1 The cDNA indicated in b, as figure 1 Shown in b, which includes the coding sequence for GLP-1(7-37), IP2 and restriction sites for SfoI, EcoRI and XbaI. To direct GLP-1 to the secretory pathway, a heterologous stromelysin 3 signal sequence (Acc No. NM — 005940) was used. Therefore, cDNA encoding the stromelysin signal and leader sequence was amplified by reverse transcriptase PCR from human RNA and compared with figure 1 a or figure 1 The constructs of b are used together to form separately figure 1 c and figure 1 Constructs shown in d.

[0233] Will figure 1 The HincII / EcoRI fragment of the a construct was cloned into figure 1 d sequence in the SfoI site to form the construct figure 1 e. Similarly, the figure 1 The EcoRI fragme...

Embodiment 2

[0237] Mammalian cell transfection, clone selection, and GLP-1 expression

[0238] Source of cells: HEK293 (human embryonic kidney cell line, #ACC 305, DSMZ Cell Culture Collection, Germany), AtT20 (mouse LAF1 pituitary tumor cell line, #87021902, European Cell Culture Collection, UK), hTERT-MSC cells were obtained from Prepared and provided by Prof. Kassem, Odense University Hospital, Denmark.

[0239] For transfection 10 6cells, 0.5 μg–2 μg of plasmid DNA with different GLP-1 constructs was used. Constructs were produced as described in Example 1. HEK293 cells were transfected using the standard calcium phosphate co-precipitation method as described in Current Protocols in Molecular Biology (Ausubel et al. 1994ff Harvard Medical School Vol 2., Unit 9.1). AtT20 cells were transfected using FuGene (Roche) as described in Current Protocols in Molecular Biology (Ausubel et al. 1994ff, Harvard Medical School Vol 2., Unit 9.4). Transfection of hTERT-MSC cells was performed usi...

Embodiment 3

[0244] Western blot analysis of GLP-1 peptides secreted by mammalian cells

[0245] The cell culture supernatant from GLP-1 secreting cells was separated by 10%-20% gradient SDS PAGE (120V, 90 minutes), and transferred to PVDF membrane by semi-dry blotting (2.0mA / cm2, 60 minutes) ( Immobilon-P Membrane 0.45 μm Millipore IPVH 00010). After methanol fixation and blocking (3% (w: v) BSA, 0.1% (v: v) Tween-20 in TBS solution), 1 μg / ml anti-GLP-1 antibody (HYB147-12, Antibodyshop ) overnight (o / n) immunoblotting of the membrane. After washing and incubation with 0.02 μg / ml detection antibody (Anti Mouse IgG, HRP conjugated, Perkin Elmer PC 2855-1197) for 4 hours at room temperature, chemiluminescent detection revealed the location of the protein.

[0246] Western blot analysis is shown in image 3 (1: 100 ng of synthetic GLP-1(7-37) dissolved in the supernatant of mock-transfected hTERT-MSC cells; 2: hTERT-MSC cells secreting dimeric GLP-1 from construct #217 ( Clone 79TM217 / 13...

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Abstract

The present application refers to the use of cells, e.g. mesenchymal stem cells or mesenchymal stromal cells, or any further suitable cell, encoding and secreting GLP-1, a fragment or variant thereof or a fusion peptide comprising GLP-1 or a fragment or variant thereof, for the treatment of acute myocardial infarction (AMI or Ml), wherein the cells, encoding and secreting GLP-1, a fragment or variant thereof or a fusion peptide comprising GLP-1 or a fragment or variant thereof, are encapsulated in a (spherical) microcapsule to prevent a response of the immune system of the patient to be treated. The present application also refers to the use of these (spherical) microcapsule(s) or of a pharmaceutical composition containing these cells or (spherical) microcapsule(s) for the treatment of acute myocardial infarction (AMI or Ml).

Description

technical field [0001] The present application relates to cells encoding and secreting GLP-1, fragments or variants thereof or fusion peptides comprising GLP-1 or fragments or variants thereof (such as mesenchymal stem cells or mesenchymal stromal cells or any other suitable cells) Use in the treatment of acute myocardial infarction (AMI or MI), wherein cells encoding and secreting GLP-1, fragments or variants thereof or fusion peptides comprising GLP-1 or fragments or variants thereof are encapsulated in (spherical) microspheres capsule to prevent a reaction from the immune system of the patient being treated. The present application also relates to the use of these (spherical) microcapsules or pharmaceutical compositions containing these cells or (spherical) microcapsules for the treatment of acute myocardial infarction (AMI or MI). Background technique [0002] Acute myocardial infarction (AMI or MI), more commonly known as a heart attack, is a common medical condition t...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/50C12N5/00A61P9/00A61K35/12
CPCA61L2300/25C12N5/0663C12N2510/04A61L2300/414A61K38/1866A61L2300/62A61K38/2053A61K38/195A61L27/227A61L2400/06A61K9/00A61L27/54C12N2510/02A61K38/185A61L27/3834A61K2035/126A61L2300/64A61K38/26A61K38/204A61K9/5036A61K38/19A61L2300/258A61P9/00A61P9/10A61K2300/00
Inventor 克里斯蒂娜·沃尔拉普安德鲁·伦哈德·刘易斯彼得·威廉·斯特拉特福德埃里克·索内斯
Owner BIOCOMPATIBLES UK LTD
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