Therapeutic angiogenic factors and methods for their use

A technology of angiogenesis and angiogenesis, which is applied in gene therapy, cardiovascular system diseases, medical preparations containing active ingredients, etc., and can solve problems such as the loss of polypeptide growth factor gene expression

Inactive Publication Date: 2002-11-13
ANGIOGENIX
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In contrast, in tumor cell lines as well as in solid tumors, the expression of poly

Method used

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  • Therapeutic angiogenic factors and methods for their use
  • Therapeutic angiogenic factors and methods for their use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0093] Example 1: Use of angiogenic factors in vitro

[0094] Recombinant human pleiotropin (PTN) was isolated as described by Fang et al., J. Biol. Chem., 267:25889-25897 (1992). To determine the percentage increase in proliferation of endothelial cells following in vitro stimulation with PTN, endothelial cells (HUVEC, human umbilical vein endothelial cells, American Type Culture Collection, #CRL-1730) were cultured at 10 4 Cells / well were seeded in 2 ml of F12K medium (Life Technologies (Rockville MD), #11765054 and #16140071, respectively) containing 10% fetal calf serum in 12-well tissue culture plates. After about 6 hours, the cells were attached to the culture plate, and 50 ng of PTN dissolved in 50 μl of PBS buffer (phosphate-buffered saline) was added to each well to be treated (6 treatment groups, each group n=6). An equal volume of PBS alone was added to each control well (n=6) to determine background proliferation levels. At each 24-hour time point, medium was rem...

Embodiment 2

[0095] Example 2: In vivo treatment of mouse wounds with angiogenic factors

[0096] PTN was isolated as described in Example 1. To determine the effect of topical PTN treatment in vivo on the subcutaneous vasculature of mice, matrix was injected bilaterally under the loose rib skin of 5 (n=10) BALB / c mice per group (Harlan Sprague-Dawley, Indianapolis, IN) implant. To prepare the implant, PTN protein dissolved in PBS solution (above) is mixed with Matrigel, which is liquid at room temperature TM (Collaborative Research, MA) to a concentration of 10 μg / ml. Control implants were prepared in a similar manner, but without PTN in the buffer. Since the matrix solution turns into a gel when the temperature rises above room temperature but below body temperature of 37°C, the matrix solution is injected into the subcutaneous pouch using a 16-gauge needle at 1 ml per site. At body temperature, the gel solution becomes a partially cured matrix. At each time point, the corresponding g...

Embodiment 3

[0097] Example 3: Angiogenesis in vivo using a controlled delivery matrix

[0098] PTN was obtained as described in Example 1. To determine the effect of continuous topical PTN treatment on the functional vasculature in vivo, the well known Folkman CAM (chicken chorioallantoic membrane) assay was used. After fertilization 5 days' eggs (local Leghorn white, Half Moon Bay, CA) egg shell is partly opened, Vasotrophin TM The system (Angiogenix Corporation, Burlingame, CA) was placed at the leading edge of a CAM approximately 15 mm in diameter. Vasotrophin used TM The system is a 500 μl bioerodible pellet consisting of 1 μg / ml PTN formulated into a poly(lactide-co-glycolide) matrix (PLGA, Absorbable Polymer Technologies, Birmingham, AL), or each containing 500ng PTN. A control pellet was generated in a similar manner, but without PTN. Over the next two weeks, the CAMs were observed with the naked eye, and differences in vessel growth patterns were observed, visualized by a dis...

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Abstract

The present invention provides a method of stimulating angiogenesis in a human or animal in need thereof, and also provides a composition comprising an angiogenic factor and a pharmaceutically acceptable carrier. In one embodiment, the method comprises administering to a human or other animal a therapeutically effective amount of an angiogenic factor, such as pleiotropin or a midkine protein, contained in a pharmaceutically acceptable carrier. In one embodiment, the carrier includes a controlled release matrix, such as a polymer, that allows the controlled release of angiogenic factors. The polymer is biodegradable and/or bioerodible, preferably biocompatible. Polymers useful for controlled release include, for example, poly(esters), poly(anhydrides) and poly(amino acids). Polymers include, for example, silk elastin poly(amino acid) block copolymers and poly-lactide-co-glycolide. In another embodiment, angiogenic factors may be provided in a carrier comprising liposomes, such as heterocystic liposomes. Carriers such as liposomes may contain targeting ligands capable of targeting the liposomes to predetermined sites in vivo. Angiogenic factors may be administered to the vasculature, such as the cardiovascular system or the peripheral vasculature. In preferred embodiments, the angiogenic factor is a pleiotrophin or a midkine protein. In another embodiment, there is provided a method of stimulating angiogenesis in a human or animal, the method comprising administering to the human or animal a therapeutically effective amount of a gene transfer vector contained in a pharmaceutically acceptable carrier, the gene transfer vector Can encode pleiotropin or midkine protein. Gene transfer vectors can be, for example, naked DNA or viral vectors, and can be used, for example, in combination with liposomes.

Description

technical field [0001] The present invention generally relates to the use of a therapeutic angiogenic factor, such as pleiotrophin, to promote angiogenesis for the treatment of various indications including cardiovascular disease. Background technique [0002] During embryonic and neonatal growth, polypeptide growth factors play an important physiological role in the timely development of tissues, therefore, their expression is tightly regulated. In contrast, expression of polypeptide growth factor genes is deregulated in tumor cell lines as well as in solid tumors, Cross and Dexter, Cell, 64:271 (1991). [0003] Pleiotropin (PTN) is a secreted growth factor belonging to the heparin-binding growth factor family, Lai et al., Biochem. Biophys. Res. Commun., 187:1113-1121 (1992). Originally, pleiotropin was purified from bovine uterus as a weak mitogen and from neonatal rat brain as an axon outgrowth promoter, Milner et al., Biochem. Biophys. Res. Commun., 165: 1096-1103 (1989...

Claims

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Application Information

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IPC IPC(8): A61K9/00A61K9/16A61K9/26A61K35/76A61K9/127A61K38/00A61K38/18A61K48/00A61P9/00A61P17/02A61P19/00A61P25/28A61P43/00
CPCA61K9/0024A61K9/1647A61K38/18A61K48/00A61P17/02A61P19/00A61P25/28A61P43/00A61P9/00
Inventor K·J·考雷
Owner ANGIOGENIX
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