Abstract
Adeno-associated viruses (AAV) have emerged as the lead vector in clinical trials and form the basis for several approved gene therapies for human diseases, mainly owing to their ability to sustain robust and long-term in vivo transgene expression, their amenability to genetic engineering of cargo and capsid, as well as their moderate toxicity and immunogenicity. Still, recent reports of fatalities in a clinical trial for a neuromuscular disease, although linked to an exceptionally high vector dose, have raised new caution about the safety of recombinant AAVs. Moreover, concerns linger about the presence of pre-existing anti-AAV antibodies in the human population, which precludes a significant percentage of patients from receiving, and benefitting from, AAV gene therapies. These concerns are exacerbated by observations of cellular immune responses and other adverse events, including detrimental off-target transgene expression in dorsal root ganglia. Here, we provide an update on our knowledge of the immunological and molecular race between AAV (the “hedgehog”) and its human host (the “hare”), together with a compendium of state-of-the-art technologies which provide an advantage to AAV and which, thus, promise safer and more broadly applicable AAV gene therapies in the future.
Highlights
The hallmark of gene therapy is the delivery of exogenous nucleic acids to cells with the aim to replace missing or defective genes, or to suppress (RNA interference technology) or correct deleterious ones, in order to ameliorate genetic causes of disease
The following chapters briefly summarize the current knowledge of the role of these arms in anti-associated viruses (AAV) immune response in humans before we focus on clinically relevant countermeasures
This process was shown to require type I IFN [60, 67], next to TLR9, which is secreted by plasmacytoid dendritic cells (DCs) and binds to its receptor on conventional DCs
Summary
The hallmark of gene therapy is the delivery of exogenous nucleic acids to cells with the aim to replace missing or defective genes, or to suppress (RNA interference technology) or correct (genome editing) deleterious ones, in order to ameliorate genetic causes of disease. Recombinant AAVs transduce cells akin to an infection with their parental wild-type (wt)AAVs, but they cannot integrate into the host cell chromosome in a sitespecific manner or integrate at very low frequency, due to the lack of the rep gene [25] Still, they can establish long-term transgene expression in both, animals and humans [26,27,28,29]. It was later determined that this was due to cytotoxic T-cell (CTL) responses from memory CD8+ T-cells against hepatocytes presenting AAV epitopes via major histocompatibility complex (MHC) class I [36,37,38,39] In another clinical trial using AAV8 to deliver a codon-optimized fIX gene, a short-term supply of immunosuppressants sufficed to block cellular immune responses and enabled long-term expression [27]. This review will first explore the mechanisms of anti-AAV immune responses and methods to measure them, before focusing on the multifaceted approaches to escape them in a (pre)clinical setting
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