Adeno-Associated Virus-Human Bocavirus 1 Chimeric Vectors: Ferreting Out Their Role in Airway Gene Therapy

Human bocavirus 1 (HBoV1, also referred to as primate bocaparvovirus 1 by the International Committee on Taxonomy of Viruses) is a member of the family Parvoviridae, subfamily Parvovirinae, and genus Bocaparvovirus. ^* Thus, it is related to adeno-associated viruses (AAVs), which are members of the genus Dependoparvovirus, within the same family and subfamily. Yet, unlike most AAVs, HBoV1 has a robust tropism for human airway epithelial cells. In this issue, Yan et al. demonstrate that just as recombinant AAV2 capsid genomes can be packaged into any one of a broad range of different AAV serotype and parvovirus B19 capsids, ^1,2 HBoV1 can also be used to cross-package AAV2 genomes, thus creating rAAV2/HBoV1 chimeric vectors. ³ The intent of this chimeric design is to take advantage of the high affinity of the HBoV1 capsid and the stable persistence of rAAV2 DNA cassettes. The ultimate goal would be to develop a better mechanism for gene therapy of cystic fibrosis (CF), a relatively common single-gene disorder affecting the airway epithelium. Importantly, the field of CF gene therapy has been advanced by the generation of new knockout animal models in the pig and ferret. ⁴ Ferrets in particularly are useful because the architecture of their respiratory epithelium is quite similar to humans in cellular composition and the presence of submucosal glands.

Yan et al. demonstrate in a series of studies that their rAAV2/HBoV1 vectors are capable of efficient gene transfer in ferret proximal and distal airway epithelial cells, including in air–liquid interface cultures, tracheal xenografts, and, in vivo, live ferrets. ³ As the group had previously determined, the optimized conditions included co-administration of proteasome inhibitors doxorubicin and LLnL. Their results indicated robust gene transfer with luciferase and mCherry reporters in both proximal and distal airways and the ability to re-dose effectively with a different reporter gene (Gaussia vs. Renilla luciferase) after neonatal ferret gene transfer. The characteristics of vector persistence in older animals were also studied and proved favorable.

Taken together, this work seems quite promising as a new approach to gene therapy for CF, at least providing an approach suitable for studying CFTR gene replacement in the CF ferret model in future studies. This type of study demonstrates the critical importance of developing viral vector systems with appropriate tropism for larger animals, whose characteristics more closely mimic those of humans. This also demonstrates the importance of ongoing co-development of vectors and animal models to tackle gene therapy, targeting organs with more complex architecture, such as the airway epithelium. Only through such studies can ongoing progress be made on treating single-gene disorders such as CF whose pathobiology is not at all simple.