Developing Immunologically Inert Adeno-Associated Virus (AAV) Vectors for Gene Therapy: Possibilities and Limitations

Abstract

Gene therapy has become a clinical reality as demonstrated by remarkable benefits seen in Phase I/II clinical trials for hemophilia B, lipoprotein lipase deficiency and Leber's congenital amarousis. The choice of, and the improved understanding in vector characteristics have contributed significantly to this success. The adeno-associated virus (AAV) vectors used in these trials have been long known to be relatively safe and efficacious. However, certain factors, most notably host immunity to the vector, prevent their widespread use. In patients who have pre-existing antibodies to AAV, these vectors will be rapidly cleared. Administration of a relatively high initial dose of vector to achieve and sustain a higher margin of therapeutic benefit is limited by concerns of vector dose-dependent T cell response. Frequent vector administration necessitated by the non-integrating nature of the virus is difficult due to the variable, yet significant host immunological memory. Thus generation of AAV vectors that are immunologically inert is pivotal for the long-term success with this promising vector system. Several strategies, that aim targeted disruption of antigenic sites or those that chemically modify the vectors have been proposed for host immune evasion. While these approaches have been successful in the pre-clinical model systems, this continues to be a field of intense experimentation and constant improvisation due to limited information available on vector immunology or data from human studies. This review forms a comprehensive report on current strategies available to generate immunologically inert AAV vectors and their potential in mediating longterm gene transfer.

Using injectoporation to deliver genes to mechanosensory hair cells

“…Adenovirus vectors have been used successfully to study gene function in cultured hair cells, for example, to express transmembrane channel-like 1 (TMC1) and TMC2 proteins 27,28 . However, virus production is time consuming, and viral coat proteins may cause immune responses that adversely affect cell function 29 . There are also limits to the size of the transgene that can be accommodated by the viral backbone.…”

Targeted delivery of AAV-transduced mesenchymal stromal cells to hepatic tissue forex vivogene therapy

“…It has been previously established that human pooled IgG from human donors, such as IVIG, has neutralizing antibodies (NAbs) against AAV vectors of different serotypes (Arbetman et al ., ; Calcedo et al ., ; Selot et al ., ). To evaluate the efficacy of MSC‐mediated AAV1 gene transfer in a passive immunization model, we first titrated the optimum concentration of IVIG that is effective in neutralizing AAV1 vectors in vivo .…”

Gene Therapy for Cardiomyopathies

“…Readministration remains a major challenge, because single shot solutions are counterintuitive in the era of precision or personalized medicine. Further work is therefore needed to improve viral vectors, more specifically, developing stealthier AAV vectors with the aim of optimizing vector-host interactions [59][60][61]. Low-grade immune stimulation by the vector system appears as an important point in terms of drug development to avoid severe adverse reactions.…”