Abstract
Recombinant adeno-associated virus (rAAV) vectors are a promising platform for in vivo gene therapy. The presence of neutralizing antibodies (Nab) against AAV capsids decreases cell transduction efficiency and is a common exclusion criterion for participation in clinical trials. Novel engineered capsids are being generated to improve gene delivery to the target cells and facilitate success of clinical trials; however, the prevalence of antibodies against such capsids remains largely unknown. We therefore assessed the seroprevalence of antibodies against a novel synthetic liver-tropic capsid AAV-LK03. We measured seroprevalence of immunoglobulin (Ig)G (i.e., neutralizing and nonneutralizing) antibodies and Nab to AAV-LK03 in a cohort of 323 UK patients (including 260 pediatric) and 52 juvenile rhesus macaques. We also performed comparative analysis of seroprevalence of Nab against wild-type AAV8 and AAV3B capsids. Overall IgG seroprevalence for AAV-LK03 was 39% in human samples. The titer increased with age. Prevalence of Nab was 23%, 35%, and 18% for AAV-LK03, AAV3B, and AAV8, respectively, with the lowest seroprevalence between 3 and 17 years of age for all serotypes. Presence of Nab against AAV-LK03 decreased from 36% in the youngest cohort (birth to 6 months) to 7% in older primary school-age children (9–11 years) and then progressively increased to 54% in late adulthood. Cross-reactivity between serotypes was >60%. Nab seroprevalence in macaques was 62%, 85%, and 40% for AAV-LK03, AAV3B, and AAV8, respectively. When planning for AAV gene therapy clinical trials, knowing the seropositivity of the target population is critical. In the population studied, AAV seroprevalence for AAV serotypes tested was low. However, high cross-reactivity between AAV serotypes remains a barrier for re-injection. Shifts in Nab seroprevalence during the first decade need to be confirmed by longitudinal studies. This possibility suggests that pediatric patients could respond differently to AAV therapy according to age. If late childhood is an ideal age window, intervention at an early age when maternal Nab levels are high may be challenging. Nab-positive children excluded from trials could be rescreened for eligibility at regular intervals because this status may change.
Highlights
OVER THE LAST DECADE, recombinant adeno-associated virus vectors have shown increasing promise as a platform for in vivo gene therapy
This study presents the rates of IgG and neutralizing antibodies (Nab) seroprevalence against selected wild-type and engineered AAV capsids, which are commonly used for liver-directed gene therapy, in large UK-based pediatric and adult cohorts and juvenile nonhuman primates
Anti-AAV-LK03 Nab seroprevalence rates of 67% and 91% were reported in recent studies in European (n = 21, cutoff 1:5 dilution)[39] and Chinese (n = 100, cutoff 1:20 dilution)[38] adult populations, respectively
Summary
OVER THE LAST DECADE, recombinant adeno-associated virus (rAAV) vectors have shown increasing promise as a platform for in vivo gene therapy. The presence of antibodies with neutralizing effect (i.e., preventing target cell transduction) has been recognized as a major limiting factor for gene delivery in vivo[18] even at low titers such as 1 in 5 (1:5) dilution.[19,20,21] the presence of neutralizing antibodies (Nab) against the vector capsid is widely considered to be an exclusion criterion for recruitment into clinical trials.[22] Since the seroprevalence against wild-type AAV in humans varies from 40% for AAV8 to 70% for AAV1 and AAV2,23 this substantially reduces the proportion of the population that could benefit from AAVbased therapeutics. Geographic location, and capsid species-of-origin influence seroprevalence rates.[24,25] Cross-reactivity between serotypes is commonly >50%.26
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