Helper dependent adenovirus vectors: progress and future prospects.

Sixteen years after Graham and coworkers described the most used system for generating helper-dependent adenovirus (HDAd) vectors, production systems have evolved considerably, and most resulting preparations have titres of 1 × 10(13) IU/ml (infection units/ml) and very low helper contamination levels (<0.1%). These advances in production, as well as the attractive characteristics of these vectors (large insert capacity and low cell immune response compared with first-generation Ad vectors) make them very interesting for many research purposes as they have become more accessible to the scientific community.

Central nervous system delivery of helper-dependent canine adenovirus corrects neuropathology and behavior in mucopolysaccharidosis type VII mice.

Canine adenovirus type 2 vectors (CAV-2) are promising tools to treat global central nervous system (CNS) disorders because of their preferential transduction of neurons and efficient retrograde axonal transport. Here we tested the potential of a helper-dependent CAV-2 vector expressing β-glucuronidase (HD-RIGIE) in a mouse model of mucopolysaccharidosis type VII (MPS VII), a lysosomal storage disease caused by deficiency in β-glucuronidase activity. MPS VII leads to glycosaminoglycan accumulation into enlarged vesicles in peripheral tissues and the CNS, resulting in peripheral and neuronal dysfunction.

Altering the Ad5 packaging domain affects the maturation of the Ad particles.

We have previously described a new family of mutant adenoviruses carrying different combinations of attB/attP sequences from bacteriophage PhiC31 flanking the Ad5 packaging domain. These novel helper viruses have a significantly delayed viral life cycle and a severe packaging impairment, regardless of the presence of PhiC31 recombinase. Their infectious viral titers are significantly lower (100-1000 fold) than those of control adenovirus at 36 hours post-infection, but allow for efficient packaging of helper-dependent adenovirus.