Nacystelyn enhances adenoviral vector-mediated gene delivery to mouse airways.
Adenoviral vector-mediated gene delivery has been vastly investigated for cystic fibrosis (CF) gene therapy; however, one of its drawbacks is the low efficiency of gene transfer, which is due to basolateral colocalization of viral receptors, immune responses to viral vectors and the presence of a thick mucus layer in the airways of CF patients. Therefore, enhancement of gene transfer can lead to reduction in the viral dosage, which could further reduce the acute toxicity associated with the use of adenoviral vectors. Nacystelyn (NAL) is a mucolytic agent with anti-inflammatory and antioxidant properties, and has been used clinically in CF patients to reduce mucus viscosity in the airways. In this study, we show that pretreatment of the airways with NAL followed by administration of adenoviral vectors in complex with DEAE-Dextran can significantly enhance gene delivery to the airways of mice without any harmful effects. Moreover, NAL pretreatment can reduce the airway inflammation, which is normally observed after delivery of adenoviral particles. Taken together, these results indicate that NAL pretreatment followed by adenoviral vector-mediated gene delivery can be beneficial to CF patients by increasing the efficiency of gene transfer to the airways, and reducing the acute toxicity associated with the administration of adenoviral vectors.
Kushwah
R
R
Physiology and Experimental Medicine Research Program, Hospital for Sick Children, and Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
Oliver
J R
JR
Cao
H
H
Hu
J
J
D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D002460:Cell Line; D003637:DEAE-Dextran / Q000008:administration & dosage; D005100:Expectorants / Q000627:therapeutic use*; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage*; D007763:Lac Operon; D008168:Lung / Q000378:metabolism* / Q000821:virology; D008239:Lysine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D051379:Mice; D008810:Mice, Inbred C57BL; D013194:Staining and Labeling; D014161:Transduction, Genetic / Q000379:methods
D005100:Expectorants; C086501:N-acetylcysteine lysinate; D003637:DEAE-Dextran; D008239:Lysine; D000111:Acetylcysteine