Challenges and Prospects for Helper-Dependent Adenoviral Vector-Mediated Gene Therapy

Abstract

Helper-dependent adenoviral (HDAd) vectors that are devoid of all viral coding sequences are promising non-integrating vectors for gene therapy because they efficiently transduce a variety of cell types in vivo, have a large cloning capacity, and drive long-term transgene expression without chronic toxicity. The main obstacle preventing clinical applications of HDAd vectors is the host innate inflammatory response against the vector capsid proteins that occurs shortly after intravascular vector administration and result in acute toxicity, the severity of which is dose dependent. Intense efforts have been focused on elucidating adenoviral vector-host interactions and the factors involved in the acute toxicity. This review focuses on the recent acquisition of data on such interactions and on strategies investigated to improve the therapeutic index of HDAd vectors.

Keywords: adenovirus; gutless vectors; helper-dependent adenoviral vectors; liver directed gene therapy.

Figure 1

Schematic representation of the liver microarchitecture and the hurdles to efficient Ad vector-mediated hepatocyte gene therapy. Systemic delivery of Ad vector particles is hampered by binding of plasma proteins, Kupffer cell uptake, and limited permeability of endothelial cells. In the bloodstream, coagulation factor X (FX) binds with high affinity to the Ad capsid and protects from IgM and complement binding. Complement receptors bind to complement proteins bound either directly or indirectly to Ad particles. Vector particles osponized by pentameric IgM, monomeric IgG, or complement factors are recognized by different receptors (FcR, CR) on Kupffer cells. Kupffer cells and endothelial cells also express SR-A and SREC-I that bind Ad5 particles based on negative-charge interactions. The size of liver sinusoidal fenestrations affects the efficiency of Ad-mediated hepatocyte transduction. Abbreviations: HPSG, heparan sulfate proteoglycans; FX, factor X; FcR, Fc-receptor; SR-A, scavenger receptor-A; SREC-I, scavenger receptor expressed by endothelial cells 1; CR, complement receptors.