Vectors for airway gene delivery

Delivery of genes to the airway epithelium for therapeutic purposes seemed easy at first, because the epithelial cells interface with the environment and are therefore accessible. However, problems encountered were more substantial than were originally expected. Nonviral systems may be preferred for long-term gene expression, for they can be dosed repeatedly. Two nonviral gene transfer systems have been in clinical trials, lipid-mediated gene transfer and DNA nanoparticles. Both have sufficient efficiency to be candidates for correction of the cystic fibrosis defect, and both can be dosed repeatedly. However, lipid-mediated gene transfer in the first generation provokes significant inflammatory toxicity, which may be engineered out by adjustments of the lipids, the plasmid CpG content, or both. Both lipid-mediated gene transfer and DNA nanoparticles in the first generation have short duration of expression, but reengineering of the plasmid DNA to contain mostly eukaryotic sequences may address this problem. Considerable advances in the understanding of the cellular uptake and expression of these agents and in their practical utility have occurred in the last few years; these advances are reviewed here

Nonviral Gene Delivery: Principle, Limitations, and Recent Progress

Gene therapy is becoming a promising therapeutic modality for the treatment of genetic and acquired disorders. Nonviral approaches as alternative gene transfer vehicles to the popular viral vectors have received significant attention because of their favorable properties, including lack of immunogenicity, low toxicity, and potential for tissue specificity. Such approaches have been tested in preclinical studies and human clinical trials over the last decade. Although therapeutic benefit has been demonstrated in animal models, gene delivery efficiency of the nonviral approaches remains to be a key obstacle for clinical applications. This review focuses on existing and emerging concepts of chemical and physical methods for delivery of therapeutic nucleic acid molecules in vivo. The emphasis is placed on discussion about problems associated with current nonviral methods and recent efforts toward refinement of nonviral approaches

Induction of metabolic syndrome by excess fructose consumption

Fructose is an important nutritive component of foods such as honey and fruit, but this easily available sweetener may contribute to increased caloric consumption from overeating. Fructose is now a major component of the Western diet, with increased consumption associated with obesity, metabolic syndrome, and cardiovascular disorders in observational and short-term intervention studies, mainly in animal models. Rodent studies have identifi ed possible mechanisms for the adverse effects of fructose when ingested in large amounts. Fructose promoted de novo lipogenesis, infl ammation, and increased sympathetic tone. These mechanisms induced hepatic insulin resistance, increased total and visceral fat mass with accumulation of ectopic fat in the liver and skeletal muscle, and dyslipidemia. Fructose reduced leptin and insulin signals for satiety, caused structural and functional damage to the heart and blood vessels, and disrupted the diversity of the gut microbiota. These early effects may initiate the development of the metabolic syndrome. Despite this evidence from rodents, there are few long-term intervention studies in humans, especially at a moderate dose. The defi nition of prudent fructose consumption is needed, but this will require carefully controlled dose–response studies in humans

Nonviral gene delivery: What we know and what is next

Gene delivery using nonviral approaches has been extensively studied as a basic tool for intracellular gene transfer and gene therapy. In the past, the primary focus has been on application of physical, chemical, and biological principles to development of a safe and efficient method that delivers a transgene into target cells for appropriate expression. This review summarizes the current status of the most commonly used nonviral methods, with an emphasis on their mechanism of action for gene delivery, and their advantages and limitations for gene therapy applications. The technical aspects of each delivery system are also reviewed, with a focus on how to achieve optimal delivery efficiency. A brief discussion of future development and further improvement of the current systems is intended to stimulate new ideas and encourage rapid advancement in this new and promising field