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Abstract

Grant Number:	5R44HL065791-03
PI Name:	SANDERS, JONATHAN R.
PI Email:	rsanders@generxplus.com
PI Title:
Project Title:	Improved Plasmid/Liposome Administration to the Lungs

Abstract: DESCRIPTION (provided by applicant): A major impediment to the successful use of aerosol gene therapy for the treatment of lung diseases is the lack of an efficient and safe aerosol delivery strategy. When the transgene vector is a cationic liposome/plasmid DNA complex, factors that must be considered in designing the optimal aerosol device are the intrinsic instability of the liposome/plasmid complex, physical disruption of the complex upon aerosolization, and maximizing the amount of the complex deposited in the lung while minimizing contamination of the environment with exhaled transgene vector. Under support of a Phase I SBIR, we have systematically evaluated how physical stability and the process of aerosolization affects transfection efficacy in airway cells in vitro. These data have permitted us to design a liposome/plasmid DNA aerosolization device for use in humans with pulmonary and pulmonary vascular disease, which we believe could deliver potentially therapeutic genes to the airspaces in a highly efficient and safe manner. The purpose of this Phase II application is to develop a prototype plasmid/liposome delivery device to the point that it is testable in humans. Specifically, we propose to use this strategy to deliver the gene encoding the cyclooxygenase (COX) enzyme to the distal airspaces of humans with primary pulmonary hypertension (PPH). In order to achieve this goal, we will quantify pulmonary deposition, distribution, and clearance profiles in normal sheep of aerosols with different particle sizes aiming to maximize distal deposition; test strategies for improving the physical stability of the complex; and using the optimized delivery system, determine the efficacy of delivering the COX gene to distal airspaces in reversing pulmonary hypertension in the sheep model of PPH. PROPOSED COMMERCIAL APPLICATIONS: This project is part of a geneRx+ program to develop aerosol devices to efficiently deliver plasmid DNA/fiposome complexes to the distal airspaces of the human lung in order to treat both primary and secondary pulmonary hypertension. The partnership between geneRx+ and Profile Therapeutics represents a unique alliance, the goal of which is to develop aerosol devices specifically designed to efficiently nebulize plasmid/liposomes complexes to humans. If our concepts prove correct, then these devices will become the industry benchmark for transgene/liposome aerosol delivery devices.

Thesaurus Terms:
aerosol, gene delivery system, gene targeting, liposome, nonhuman therapy evaluation, plasmid, prostaglandin endoperoxide synthase, pulmonary hypertension, technology /technique development
gene expression, gene therapy, inhalation drug administration, transfection /expression vector
biotechnology, sheep, tissue /cell culture

Institution:	GENERX+, INC.
	3200 WEST END AVE, STE 500
	NASHVILLE, TN 372011322
Fiscal Year:	2003
Department:
Project Start:	01-SEP-2000
Project End:	31-DEC-2004
ICD:	NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
IRG:	ZRG1

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