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Combination of a nucleic acid and a vasoactive agent for enhanced gene delivery

An angiogenesis and blood vessel technology, applied in vector-mediated gene delivery, adenovirus constructs, treatment of peripheral vascular disease and heart disease, technology for delivering required genes, vector constructs, can solve systemic expression of transgenes, etc. question

Inactive Publication Date: 2001-06-27
RGT UNIV OF CALIFORNIA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Failure to do so can lead to systemic expression of the transgene and cause a host of problems

Method used

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  • Combination of a nucleic acid and a vasoactive agent for enhanced gene delivery
  • Combination of a nucleic acid and a vasoactive agent for enhanced gene delivery
  • Combination of a nucleic acid and a vasoactive agent for enhanced gene delivery

Examples

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Embodiment 1

[0057] To facilitate the understanding of the invention, the following examples are provided to describe the results of a series of experiments. Of course, the experiments related to the present invention should not be regarded as particularly limiting the present invention, and modifications to the present invention, now known or later produced, are readily made by those skilled in the art, and fall within the scope of the invention described herein and hereinafter required. within the scope of the present invention. Example 1: Adenovirus constructs

[0058] A helper-independent replication-deficient human adenovirus 5 system was used. The target genes are lacZ and FGF-5. Release the full-length cDNA of human FGF-5 from the plasmid pLTRI22E (Zhen et al., Molecular Cell Biology, 8:3487,1988) in the form of a 1.1kb EcoRI fragment, which includes the gene open reading frame of 981bp, and clones the fragment into In the polylinker of plasmid ACCMVPLPA, which contains the CMV p...

Embodiment 2

[0060] Adult rat cardiomyocytes were prepared by Langendorf perfusion with collagenase-containing perfusate according to standard methods. The rod-shaped cells were cultured on a culture plate covered with laminin, and after 24 hours, the cells were infected with the adenovirus encoding β-galactosidase obtained in Example 1, and the multiplicity of infection was 1:1. After an additional 36 hours, cells were fixed with glutaraldehyde and incubated with X-gal. Following infection with recombinant adenovirus, typically 70-90% of adult cardiomyocytes express the β-galactosidase transgene. No cytotoxicity was observed when the MOI was 1-2:1.

Embodiment 3

[0061] Example 3: Myocardium in pigs

[0062] According to the method of Example 1, the adenovirus vector encoding β-galactosidase obtained in Example 1 was propagated in 293 permissive cells, and purified by CsCl gradient ultracentrifugation so that the final virus titer was 1.5×10 10 virus particles. Anesthetized and ventilated 40kg pigs were subjected to thoracotomy, a 26-gauge butterfly needle was inserted into the middle of the left anterior descending (LAD) coronary artery, and 2ml of vehicle (1.5×10 10virus particles). Suture the chest and allow the animal to recover. On day 4 post-injection, animals were sacrificed. Hearts were fixed with glutaraldehyde, sectioned and incubated with X-gal for 16.5 hours. After embedding and sectioning, tissues were counterstained with eosin.

[0063] Microscopic analysis of tissue sections (transmural sections of the LAD bed 96 hours after intracoronary injection of adenovirus containing lacZ) showed that substantial gene transfer...

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PUM

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Abstract

Transgene-inserted vectors are effectively used for in vivo gene therapy for peripheral vascular disease, heart disease and other conditions, by direct injection of the vector into arteries supplying the tissue to be targeted, preferably in combination with a vasoactive agent that is infused into the artery prior to or coincident with delivery of the vector.

Description

[0001] background field of invention [0002] The present invention relates to gene therapy, and more particularly to viral-mediated and other forms of gene therapy, and to certain vector constructs, including adenoviral constructs, and techniques for delivering desired genes. The present invention relates more particularly to vector-mediated gene delivery useful for promoting cardiac angiogenesis, and to methods of treating peripheral vascular disease and heart disease, including myocardial ischemia and other diseases, using such vectors and gene delivery techniques . technical background [0003] According to the report of the American Heart Federation (statistical supplement in 1995), about 60 million adults in the United States suffer from cardiovascular disease, of which 11 million adults suffer from coronary heart disease. Cardiovascular disease kills approximately 1 million Americans each year, accounting for 40% of total mortality. In 1995, 1.5 million adults in th...

Claims

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Application Information

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IPC IPC(8): A61K35/76A61K38/22A61K45/00A61K48/00A61P9/00
CPCA61K48/0083A61K48/0075A61P9/00A61P9/10A61K48/00
Inventor H·K·哈蒙德
Owner RGT UNIV OF CALIFORNIA
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