When the immunosuppression protocol changed the starting date and added methylprednisolone to the combination (63), humoral and cellular responses remained the same as the previous study
When the immunosuppression protocol changed the starting date and added methylprednisolone to the combination (63), humoral and cellular responses remained the same as the previous study. highlight important milestones along the way. Keywords: adeno-associated virus (AAV), gene therapy, immunity, toxicity, immunosuppressant, capsid engineering, exosome, CpG 1 Introduction Adeno-associated virus (AAV) is a replication-defective virus that infects vertebrates, including human and non-human primates (1). The genome PJ34 of AAV is PJ34 approximately 4.8 kb of single-stranded DNA flanked by inverted terminal repeats (ITRs), which H3/h are essential for its life cycle (2). AAV has been associated with no known diseases for long, however, a recent study suggested a potential involvement of AAV in a hepatitis outbreak in Scotland (3). Due to its low pathogenicity and risk of insertional mutagenesis, AAV has been developed as biological nanoparticles for delivery of gene therapy (4). Starting from the late 90s, there have been gene therapy clinical trials using AAV delivery (AAV gene therapy for cystic fibrosis) (5). Until now, there have been over 100 clinical trials using wild-type and engineered AAV vectors (6). The first approved AAV gene therapy drug was Glybera for treating lipoprotein lipase deficiency using AAV1 vector (7), which was approved in Europe in 2012. Then, Luxturna, an AAV2-based gene therapy for retinal diseases (8), was approved in the USA in 2017, and Zolgensma, an AAV9-based gene therapy for spinal muscular atrophy in the USA in 2019 (9). The clinical and commercial success of AAV gene therapy encouraged a rapid clinical development. However, among the ever-increasing clinical development of AAV gene therapy, serious adverse events and toxicity, mostly due to immunity elicited by AAV delivery, were observed. Safety concerns culminated when a clinical trial (NCT03199469) for X-linked myotubular myopathy (XLMTM) reported 4 patient deaths, presumably due to hepatotoxicity (10). Further, incidence of hepatocellular carcinoma (11), elevated liver enzymes (12), MRI abnormalities (13), and dorsal root ganglia (DRG) degeneration (14) were reported from multiple clinical trials. It is of particular interest to highlight patient death cases associated with AAV delivery (summarized in Table?1 ). Due to the small sample size, it may be premature to draw clear conclusions. Yet, these cases more frequently occurred in CNS and muscular diseases and were associated with a high dose. In light of this, FDA organized a two-day Cellular, Tissue, and Gene Therapies Advisory Committee (CTGAC) meeting focused on addressing AAV toxicity issues in 2021. In addition to toxicity, AAV immunity may be also responsible for loss of efficacy over time due to promoter silencing or T cell-mediated elimination of transgene-expressing cells (22). Table?1 Patient death cases that occurred in AAV trials. (60). Similarly, another study in human patients found that tacrolimus impaired Tregs proliferation, function, and phenotype, while rapamycin had beneficial effects on Tregs (61). In contrast, the combined use of tacrolimus and anti-CD4 antibody reduced antibodies against AAV capsids and transgene products and induced immune tolerance in mice (62). However, these results could not completely rule out the possibility of the inhibitory effects of tacrolimus on Tregs because tacrolimus was used in combination with another immunosuppressant in this study. Ciclosporin and MMF were used in combination in clinical studies of Glybera, which was the first approved gene therapy product in Europe (7, 63). In all patients, anti-AAV antibodies were not affected by immunosuppressants, and T cell response was observed in most patients (7). When PJ34 the immunosuppression protocol changed the starting date and.