Abstract
Advances in DNA- and RNA-based technologies have made gene therapy suitable for many lung diseases, especially those that are hereditary. The main objective of gene therapy is to deliver an adequate amount of gene construct to the intended target cell, achieve stable transduction in target cells, and to produce a clinically therapeutic effect. This review focuses on the cellular organization in the normal lung and how gene therapy targets the specific cell types that are affected by pulmonary disorders caused by genetic mutations. Furthermore, it examines the pulmonary barriers that can compromise the absorption and transduction of viral vectors and genetic agents by the lung. Finally, it discusses the advantages and limitations of direct intra-tracheal gene delivery with different viral vectors in small and large animal models and in clinical trials.
Highlights
There are no current conventional pharmacological treatments that can act effectively on intracellular targets
Gene therapy approaches that can be well suited for hereditary lung diseases with monogenetic mutations are especially attractive given that the correction of autosomal recessive or dominant disorders could be resolved through the exogenous delivery of the wild-type gene
Cystic fibrosis trans-membrane conductance regulator (CFTR) gene has a cDNA of 4450 bp, the application of associated virus (AAV) viral vector in CFTR is limited
Summary
There are no current conventional pharmacological treatments that can act effectively on intracellular targets. A great knowledge base is currently accumulating addressing the challenges associated with this technology Another interesting application of AAV vector is CRISPR/Cas delivery to program genetic and epigenetic manipulations [3,4]. The CRISPR/Cas genome-editing system has been rapidly developed and is widely used in all human stem cell studies In recent years, this system has changed the field of translational stem cell and gene therapy research. Cystic fibrosis trans-membrane conductance regulator (CFTR) gene has a cDNA of 4450 bp, the application of AAV viral vector in CFTR is limited. To address this problem, strategies based on trans-splicing and homologous recombination were developed [6]. Other studies have produced AAV vectors with a CFTR cDNA with a deletion at the N terminal, the regulatory domain or missing other transmembrane domains of CFTR These deletions did not alter the function of the CFTR gene [8]
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