Immune responses to adeno-associated virus and its recombinant vectors

Immune responses to gene therapy vectors: influence on vector function and effector mechanisms

“…A humoral response to human factor IX has been found in mice after intramuscular administration, but not intrahepatic administration, of AAV-human FIX. 44 One possible explanation is that tolerance to FIX may occur with the high FIX levels produced after intrahepatic injection but not with the lower levels obtained after intramuscular administration. In addition, FIX is produced naturally in the liver but not in the muscle.…”

Library selection and directed evolution approaches to engineering targeted viral vectors

“…Despite these advantageous properties, AAV suffers from several shortcomings, including the inability to target delivery to specific cell types (Muzyczka and Warrington, 2005), inefficient gene delivery to a number of ''nonpermissive'' cell types (Hughes et al, 2002;Ponnazhagan et al, 1996;Smith-Arica et al, 2003;Stacchini et al, 1999), a limited packaging insert size (Dong et al, 1996), and the prevalence of pre-existing immunity to human AAV serotypes in the human population (Moskalenko et al, 2000;Sun et al, 2003).…”

“…Directed evolution has recently been applied to address another challenge with AAV vectors: preexisting immunity. The majority of the human population has previously been exposed to numerous serotypes, and as a result a large fraction of the future potential patient pool harbors neutralizing antibodies that can greatly reduce gene transfer in vivo (Sun et al, 2003). Furthermore, even serotypes that activate distinct sets of B cells can still share T cell epitopes (Mingozzi et al, 2007), also a challenging problem to address.…”

Virology and immunology of gene therapy, or virology and immunology of high MOI infection with defective viruses

“…5,12,13 Of further importance to the field, this issue explores how inflammatory and immune responses will vary, even for the same vector, depending on the target organ being injected and transduced. 6,11,13 Thus, this special issue examines immune responses to vectors infecting different tissues, that is, muscle, 9 liver, 10 eye, 11 and brain. 6 Main themes of this issue include early inflammatory responses and signaling pathways activated by viral vectors; 4 how viral vectors stimulate the release of inflammatory mediators, cytokines, and 9 the mechanisms by which the innate and/or adaptive arm of the immune response can inhibit transgene expression (or eliminate transduced cells).…”