Neutralizing antibodies against adeno-associated viruses in inflammatory bowel disease patients: Implications for gene therapy

Abstract

Background: Inflammatory bowel diseases (IBDs) are comprised of two major disorders: Crohn's disease (CD) and ulcerative colitis (UC). No curative treatment options are available, but gene therapy may offer an alternative therapeutic approach. For this a safe and reliable vector is needed. The adeno‐associated viruses (AAV) have attracted considerable interest as gene therapy vectors. However, neutralizing antibodies (nAb's) made in response to wildtype AAV have been associated with a partial to complete block of transduction in case of reexposure. Therefore, and in order to define AAV vector candidates to treat IBD patients, we characterized preexisting humoral responses to AAV in this population. Methods: We measured circulating antibodies against AAV serotypes 1, 2, 3, 4, 5, 6, and 8 using a previously established virus neutralization assay. In all, 100 healthy donors and 200 IBD patient's serum samples (101 CD and 99 UC) were analyzed. Results: A significant difference was detected in the prevalence of nAb's for AAV types 1, 5, 6, and 8 between the healthy donors and the patient population. Furthermore, various disease phenotypic characteristics correlated with the prevalence of nAb's to all the serotypes studied. Conclusions: Our study establishes a foundation for the development of an AAV‐based gene therapy approach as a novel treatment for IBD. Furthermore, we show a relationship between disease phenotype in IBD patients and the humoral immune response to AAV. (Inflamm Bowel Dis 2011;)

Humoral Immune Response to AAV

“…The health status of the target population may also impact the prevalence of AAV NAbs, especially in those subjects with a compromised immune system. These subjects had a lower prevalence of AAV NAbs when compared to the healthy population (32, 55). …”

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).…”

Generation and characterization of anti-Adeno-associated virus serotype 8 (AAV8) and anti-AAV9 monoclonal antibodies

“…However, AAV elicits both a cellular and humoral immune response which must be overcome for improved vector efficacy. In the general population, ~40–70% of individuals have been exposed to AAVs (Blacklow et al 1968; Boutin et al 2010; Calcedo et al 2011; Calcedo et al 2009; Liu et al 2013), and a significant number of potential patients already harbor pre-existing antibodies to AAVs (Ferreira et al 2014; Halbert et al 2006; Li et al 2012; van der Marel et al 2011). These pre-existing antibodies have been shown, even at low levels, to prevent successful gene delivery (Hurlbut et al 2010; Manno et al 2006; Scallan et al 2006; Wang et al 2011).…”