The prevalence of neutralizing antibodies against adeno‐associated virus capsids is reduced in young Japanese individuals

Abstract

Pre-existing antibodies against adeno-associated virus (AAV), caused by natural AAV infections, interfere with recombinant AAV vector-mediated gene transfer. We studied the prevalence of neutralizing antibodies against AAV serotypes 1, 2, 5, 8, and 9 in healthy subjects (n = 85) and hemophilia patients (n = 59) in a Japanese population. For healthy subjects, the prevalence of neutralizing antibodies against AAV serotypes 1, 2, 5, 8, and 9 was 36.5%, 35.3%, 37.6%, 32.9%, and 36.5%, respectively, while that in hemophilia patients was 39.7%, 28.8%, 35.6%, 32.9%, and 27.4%, respectively. There was no difference in the prevalence of neutralizing antibody against each AAV serotype between the healthy subjects and the hemophilia patients. The prevalence of neutralizing antibodies against all AAV serotypes increased with age in both healthy subjects and hemophilia patients. High titers of neutralizing antibodies against AAV2 (≥1:224) and AAV8 (≥1:224) were more evident in older individuals (≥42 years old). Approximately 50% of all screened individuals were seronegative for neutralizing antibodies against each AAV tested, while approximately 25% of individuals were seropositive for each AAV serotype tested. The prevalence of seronegativity for all AAV serotypes was 67.0% (healthy subjects, 68.6%; hemophilia patients, 65.0%) and 18.6% (healthy subjects, 20.5%; hemophilia patients, 15.7%) in young (<42 years old) and older subjects (≥42 years old), respectively. The findings from this study suggested that young subjects are more likely to be eligible for gene therapy based on AAV vectors delivered via an intravascular route because of the low prevalence of antibodies to AAV capsids.

Adenovirus‐associated antibodies in UK cohort of hemophilia patients: A seroprevalence study of the presence of adenovirus‐associated virus vector–serotypes AAV5 and AAV8 neutralizing activity and antibodies in patients with hemophilia A

“…Evidence from healthy individuals in Japan showed that AAV infection occurred in childhood and seropositivity subsequently decreased, however there was a second increase of seropositivity after 30 years of age . Similarly, another Japanese study of healthy as well as hemophilia patients observed an increase in seropositivity with age …”

CRISPR/Cas9-mediated genome editing via postnatal administration of AAV vector cures haemophilia B mice

“…In the current study, we administrated a 5% vector dose to newborn mice and obtained the same treatment effects. Finally, the beneficial effects of using an AAV vector is more likely in younger patients because of the lower frequency of anti-AAV neutralizing antibody 30 .…”

The Current and Future Landscape of SERCA Gene Therapy for Heart Failure: A Clinical Perspective

“…Globally, there is a wide variation in the prevalence of neutralizing antibodies to AAV1, ranging from 13% to 79%. 76,77,79,81,82 The exact effect of neutralizing antibodies on the success of AAV-delivered gene therapy is largely unknown. Our group is currently undertaking a study that will hopefully address the effect of neutralizing antibodies on transduction in humans (SERCA-LVAD-ClinicalTrials.gov id: NCT00534703).…”