Overview Of Gene Vector Systems

DNA vectors consist of two major components: the gene expression system and the carrier. The gene expression system contains regulatory sequences and a nucleic acid sequence that codes for the therapeutic protein. Expression of the therapeutic gene is controlled by promoter regions to regulate protein expression [15]. Some promoters are tissue-specific, which allows one level of control over targeting gene expression [16]. In viral vectors, a portion of the viral genome is replaced by sequences coding for the therapeutic protein. Nonviral vectors generally use plasmid DNA (pDNA).

The gene carrier is typically composed of a viral capsid or, in the case of nonviral delivery systems, a lipid, polymer, protein, peptide, or multivalent cation. For recent reviews of nonviral gene carriers, the reader is referred to Refs. 10 and 17. The carrier is meant to protect DNA from degradation by enzymes and/or low pH, found in various body fluids, the extracellular matrix, cytoplasm, and lysosomes [17]. Carriers can also be modified to target specific cells using receptor-ligand interactions (for reviews see Refs. 18 and 19). Some vector strategies used for gene delivery are illustrated in Fig. 1.

The ideal method of DNA delivery should maintain the integrity of the gene and yield high gene expression in the target tissue without compromising the safety of the patient. Genetically engineered viruses, commonly used in clinical and preclinical pulmonary gene therapy protocols, are based on vectors that have evolved over millions of years to produce high levels of gene expression. As a result, viral vectors are easily the most advanced and most effective in terms of gene delivery. Of the 600 completed, ongoing, or pending gene therapy clinical trials recorded in September 2001, 72% involved a viral vector [2]. Cationic liposomes were the next most popular vector (13%). Unfortunately, some viral vectors have been associated with inflammatory immune responses [20-25], which can be detrimental to the health of patients suffering from lung diseases such as cystic fibrosis, chronic obstructive pulmonary disorder, and asthma. A clinical trial involving an adenovirus gene vector injected into the hepatic blood vessel resulted in the death of a teenage boy due to acute respiratory distress syndrome (ARDS) in September 2000. Analysis showed that the vector caused systemic inflammatory response syndrome (SIRS), which is associated with ARDS [26]. In the wake of this tragedy, there has been an increased focus on the development of safer gene delivery systems to complement the highly efficient viral vectors.

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