Table 1 Gene therapy approaches used in preclinical ALI/ARDS models

Viral vector-delivered gene therapy

   Adenoviral vectors (dsDNA genome)

Relatively easily produced Efficiently transfect lung epithelium [14, 16] Can deliver larger genes Well tolerated in lower doses [1, 3]

Immunogenic [14]

Adenoviral transfer of genes for a surfactant enzyme [49], angiopoietin-1 [51], HSP-70 [52], apolipoprotein A-1 [53], and Na⁺,K⁺-ATPase pump [55] genes attenuate experimental ALI Adenoviral delivery of IL-10 gene attenuates zymosan ALI at low doses, but is harmful at high doses [58]

   Adeno-associated virus vectors (ssDNA genome)

Good safety profile; less immunogenic Inherently replication deficient AAV-5 and AAV-6 lung epithelial tropism [10, 11] Transduce nondividing cells Long-lived gene expression Used in clinical trials for CF [12, 13]

Limited transgene size Difficult to produce in large quantities

AAV vector gene transfer demonstrated in multiple lung cell types including progenitor cells in both normal lungs and following naphthalene-induced ALI [20]

   Lentivirus vectors (RNA genome)

Transduce nondividing cells [25] Integrate stably but randomly into the genome

Oncogenesis risk due to integration into genome [26, 27]

Lentiviral transfer of shRNA to silence CD36 gene expression suppresses silica-induced lung fibrosis in the rat [35]

Nonviral gene-based strategies

   Plasmid transfer (closed dsDNA circles)

Easily produced at low cost

No specific cell targeting Very inefficient

Electroporation-mediated gene transfer of the Na⁺,K⁺-ATPase rescues endotoxin-induced lung injury [60]

Nonviral DNA complexes

(lipoplexes or polyplexes)

Complexes protect DNA Complexes facilitate cellular targeting [31]

Less efficient than viral vectors

Cationic lipid-mediated transfer of the Na⁺,K⁺-ATPase gene ameliorated high-permeability pulmonary edema [59] Lipoplex-delivered IL-10 gene decreased CLP-induced ALI [61] Systemic cationic polyethylenimine polyplexes incorporating indoleamine-2,3-dioxygenase decreased ischemia-reperfusion ALI [62]

   DNA and RNA oligonucleotides (siRNA, shRNA, decoy oligonucleotides)

Easily produced at low cost Smaller molecules that can easily enter cells Target regulation of specific genes

No specific cell targeting

Specific siRNAs reduce inflammation-associated lung injury in humans [33] and in animal models [28, 34] shRNA-based approaches have reduced lung injury in animal models [35, 36]

Cell-delivered gene therapy

   Mesenchymal stem/stromal cells

Systemic or intrapulmonary delivery Strategy used in human studies [41]

Relatively expensive

MSCs expressing angiopoeitin-1 attenuate endotoxin-induced ALI [40] Bone marrow stem cells expressing keratinocyte growth factor via an inducible lentivirus protects against bleomycin-induced lung injury [66]

   Fibroblasts

Systemic delivery Less expensive

Fibroblasts expressing angiopoeitin-1 attenuate endotoxin induced ALI [40]