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Methods for repairing tissue damage using protease-resistant mutants of stromal cell derived factor-1

A tissue damage, protease technology, applied in the direction of peptide/protein components, anti-inflammatory agents, drug combinations, etc., can solve problems such as insufficient SDF-1 availability

Inactive Publication Date: 2016-10-12
PROVASCULON
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

These studies suggest that deficiencies in naturally occurring myocardial repair processes may be due in part to insufficient SDF-1 availability

Method used

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  • Methods for repairing tissue damage using protease-resistant mutants of stromal cell derived factor-1
  • Methods for repairing tissue damage using protease-resistant mutants of stromal cell derived factor-1
  • Methods for repairing tissue damage using protease-resistant mutants of stromal cell derived factor-1

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0149] Example 1. Delayed and IV dosing of protease-resistant SDF-1 variants improves cardiac function in a rodent model of ischemia-reperfusion

[0150] In the following examples, we describe experiments demonstrating that intravenous delivery and prolonged delayed administration of compositions comprising mSDF-1 peptides improve cardiac function in a model of ischemia-reperfusion.

[0151] Anesthetize the rat using 0.05 mg / kg buprenorphine and 2-3% isoflurane. After cannulation, a thoracotomy was performed between the 4th and 5th ribs, and the left anterior descending coronary (LAD) was ligated for 90 minutes. After 90 minutes, the suture was removed from the LAD to initiate reperfusion in the infarcted area. The rat's chest and skin were then closed. The mSDF-1 peptide was administered by intravenous injection 7 days after infarction (>15 rats / group). For intravenous injection, 100 µl of PBS containing S-SDF-1 (S4V) (at doses of 0, 0.1 and 1.0 mg / kg) was injected into th...

Embodiment 2

[0155] Example 2. Delayed and IV administration of protease-resistant SDF-1 variants improves cardiac function in a porcine ischemia-reperfusion model

[0156] We also evaluated the effect of intravenous delivery and delayed dosing of compositions comprising mSDF-1 peptides on cardiac function in a mini Yucatan pig infarction model.

[0157] In these experiments, pigs were anesthetized and their left anterior descending (LAD) coronary artery was occluded by a balloon catheter. Ninety minutes later, the balloon catheter was removed from the LAD to initiate reperfusion in the infarcted area. The breast and skin of the pig were then closed. A randomized blinded study was performed in which pigs were given a first dose of mSDF-1 peptide (at 1 mg / kg or 3 mg / kg) or a PBS control via intracoronary administration immediately after ischemia (for three groups in each, n = 5 pigs). At 4 weeks (one month) after infarction, a second dose of mSDF-1 peptide (at 1 mg / kg or 3 mg / kg) or PBS ...

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Abstract

The present invention features methods for treating or ameliorating tissue damage using intravenous administration of compositions (for example, isolated peptide compositions or stem cells expressing such peptides) that include stromal cell derived factor-1 (SDF-1 ) peptides or mutant SDF-1 peptides that have been mutated to make them resistant to protease digestion, but which retain chemoattractant activity.

Description

Background of the invention [0001] In general, the invention relates to methods of repairing tissue damage using SDF-1 or protease-resistant mutants of stromal cell-derived factor-1 (SDF-1). [0002] SDF-1 (also known as CXCL12) is a 68 amino acid member of the chemokine family, which is used for resting T-lymphocytes, monocytes and CD34 + Chemoattractants for stem cells. SDF-1 is produced in several forms: SDF-1α (CXCL12a), SDF-1β (CXCL12b) and SDF-1γ as a result of differential splicing of mRNA. The sequences of SDF-1α and SDF-1β are basically identical, except that SDF-1β is extended by four amino acids (Arg-Phe-Lys-Met) at the C-terminus. The first three exons of SDF-1γ are identical to those of SDF-1α and SDF-1β. The fourth exon of SDF-1γ is located 3200 base pairs downstream from the third exon on the SDF-1 locus, and is located between the third exon and the fourth exon of SDF-1β between the exons. SDF-1 is initially produced with a signal peptide (21 amino acids i...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K38/19
CPCA61K47/68A61K47/6811A61K38/195A61P1/04A61P1/16A61P13/12A61P17/02A61P29/00A61P9/00A61P9/04A61P9/10A61P3/10A61K9/0019A61K35/28
Inventor A.桑德拉萨拉W.吴
Owner PROVASCULON