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Cell type specific and inducible promoters for vectors in gene therapy as an approach for cell targeting

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Abstract

Gene therapy is used to correct genetic defects or to deliver new therapeutic functions to the target cells. Viral vectors are employed mainly as a gene delivery system. A great variety of viral expression systems have been developed and assessed for their ability to transfer genes into somatic cells. In particular, retroviral and adenoviral mediated gene transfer have been extensively studied and improved. Preclinical and clinical studies covering a large range of genetic disorders are currently underway to solve basic issues dealing with gene transfer efficiencies, regulation of gene expression, and potential risks of the use of viral vectors. The majority of clinical gene therapy trials that employ viral vectors perform ex vivo gene transfer into target cells. The main issue in potential clinical application of gene therapy is the need for increased gene transfer efficiency and target specificity associated with regulated gene expression at therapeutically relevant levels in vivo. Gene regulatory elements, such as promoters and enhancers, possess cell type specific activities and can be activated by certain induction factors (e.g., hormones, growth factors, cytokines, cytostatics, irradiation, heat shock) via responsive elements. A controlled and restricted expression of these genes can be achieved using such regulatory elements as internal promoters to drive the expression of therapeutic genes in viral vector constructs. In addition to high level and efficient gene expression, minimizing or excluding inappropriate gene expression in surrounding nontarget cells is of great importance for numerous gene therapeutic approaches. This contribution furnishes insight into the field of cell type specific promoter and enhancer systems which have been used for targeted and inducible expression of therapeutic genes in certain genetic disorders, viral infections, and malignancies. We also discuss promoters that represent attractive candidates for the construction of viral vectors.

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Abbreviations

ADA :

Adenosine deaminase

AFP :

α-Fetoprotein

AIDS :

Acquired immunodeficiency syndrome

CAT :

Chloramphenicol acetyltransferase

CD :

Cytosine deaminase

CEA :

Carcinoembryonic antigen

DMD :

Duchenne muscular dystrophy

5-FC :

5-Fluorocytosine

HIV :

Human immunodeficiency virus

LAD :

Leukocyte adherence deficiency

LCR :

Locus control region

LTR :

Long terminal repeats

MCK :

Muscle creatinine kinase

MLV :

Moloney murine leukemia virus

MMTV :

Mouse mammary tumor virus

PEPCK :

Phosphoenolpyruvate carboxykinase

PSA :

Prostate-specific antigen

SCLC :

Small cell lung cancer cells

SLPI :

Secretory leukoprotease inhibitor

SPA/B/C :

Human surfactant protein A/B/C

TAR :

Trans-activation-responsive

TNF :

Tumor necrosis factor-α

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  1. Max Delbrück Center for Molecular Medicine, Robert-Rössle-Strasse 10, D-13122, Berlin, Germany

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Walther, W., Stein, U. Cell type specific and inducible promoters for vectors in gene therapy as an approach for cell targeting. J Mol Med 74, 379–392 (1996). https://doi.org/10.1007/BF00210632

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