Abstract
Recombinant adeno-associated virus (rAAV) has attracted a significant research focus for delivering genetic therapies to target cells. This non-enveloped virus has been trialed in many clinical-stage therapeutic strategies but important obstacle in clinical translation is the activation of both innate and adaptive immune response to the protein capsid, vector genome and transgene product. In addition, the normal population has pre-existing neutralizing antibodies against wild-type AAV, and cross-reactivity is observed between different rAAV serotypes. While extent of response can be influenced by dosing, administration route and target organ(s), these pose concerns over reduction or complete loss of efficacy, options for re-administration, and other unwanted immunological sequalae such as local tissue damage. To reduce said immunological risks, patients are excluded if they harbor anti-AAV antibodies or have received gene therapy previously. Studies have incorporated immunomodulating or suppressive regimens to block cellular and humoral immune responses such as systemic corticosteroids pre- and post-administration of Luxturna® and Zolgensma®, the two rAAV products with licensed regulatory approval in Europe and the United States. In this review, we will introduce the current pharmacological strategies to immunosuppress or immunomodulate the host immune response to rAAV gene therapy.
Highlights
Adeno-associated virus (AAV) is a 26nm, non-enveloped virus of Parvoviridae family
AAV infection is non-pathogenic in humans, initial exposure induces humoral and cellular anti-capsid response that are reactive to Adjuvant Pharmacotherapies for recombinant AAV (rAAV) Administration rAAV due to capsid similarity [4, 5]
Studies showed cross-reactive anti-capsid neutralizing antibody (NAb) present at 15 years [100], cytotoxic T lymphocytes (CTL) and Treg infiltrates at injection site after 5 years [101]; and in non-human primates (NHP) adverse effects related to high-dosage [42, 66]
Summary
Adeno-associated virus (AAV) is a 26nm, non-enveloped virus of Parvoviridae family. It is 4.7kb single-stranded DNA genome containing 4 open reading frames (ORFs) (rep, cap, aap, and MAAP) flanked by inverted terminal repeats (ITRs) [1, 2]. The viral ORFs are replaced by the desired transgene expression cassette and referred as recombinant AAV (rAAV). It has emerged as a leading vector to deliver genetic therapies due to its ability to transduce diverse cell types and safety profile. A significant obstacle in clinical delivery of rAAV is host immune response triggered by rAAV capsid, genome, and therapeutic protein produced [3]. The full clinical significance of innate response to rAAV is unclear [18], unmethylated CpG motifs in rAAV vector genome interact with toll-like receptor (TLR) 9 present in plasmacytoid dendritic cells and Kupffer cells, releasing type I interferons activating cellular and humoral responses in mouse models [19, 20], and has been suggested as the cause of loss of expression in a rAAV8 hemophilia B trial [21]. With a particular focus on licensed agents, we discuss the pharmacology of each drug (Figure 1), and their applications in enabling safe and long-term expression of rAAV gene therapies (Table 1)
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