Lung Transduction

The lung is another attractive target for gene transfer primarily because of the desire to develop gene therapy for cystic fibrosis (CF). Cystic fibrosis is caused by recessive mutations in the CF transmembrane conductance regulatory (CFTR) gene which encodes a membrane chloride channel present in the epithelium of the lung and other organs. Morbidity and mortality in CF patients is due to lung disease characterized by inflammation, obstructive mucus, and persistent infection. Helper-dependent adenoviral vector efficiently transduces airway epithelial and submucosal cells in mice following intranasal administration, and in contrast to FGAd results

In addition to long-term, chronic toxicity mediated by viral protein expression from the vector backbone, systemic administration of FGAd also results in acute toxicity. This acute toxicity occurs immediately following vector administration and is characterized by highlevel inflammatory cytokine production, consistent with activation of an acute inflammatory response.[12-15] While the precise mechanism responsible for this acute response remains to be determined, it appears to be mediated by the viral capsid in a dose-dependent manner with potentially severe and lethal consequences. Indeed, the death of a partial OTC-deficient patient, whose clinical course was marked by systemic inflammatory response syndrome (SIRS), disseminated intravascular coagulation, and multiorgan failure, was attributed to acute toxicity from the administration of a second-generation (E1- and E4-deleted) Ad vector.[16] Because the viral capsid of early generation Ad and HDAd are identical, it has been hypothesized that HDAd would also provoke an identical acute response. Indeed, this was confirmed in nonhuman primates in which dose-dependent acute toxicity, consistent with activation of the innate inflammatory immune response, was observed following systemic administration of HDAd.[17] It is important to note that robust activation of the acute inflammatory response is also observed in mice given systemic Ad. However, unlike primates, lethal SIRS does not develop in rodents, even at high doses which are lethal to primates. This may reflect species-to-species differences in the quality of the innate immune response or sensitivities of the end organs to pathologic sequelae. This likely accounts for the plethora of studies reporting negligible toxicity in mice given high-dose HDAd and underscores the importance of safety and toxicity evaluations in larger animals for all gene therapy vectors.

Getting Started With Dumbbells

Getting Started With Dumbbells

The use of dumbbells gives you a much more comprehensive strengthening effect because the workout engages your stabilizer muscles, in addition to the muscle you may be pin-pointing. Without all of the belts and artificial stabilizers of a machine, you also engage your core muscles, which are your body's natural stabilizers.

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