Inflammation in Viral Vector-Mediated Ocular Gene Therapy: A Review and Report From a Workshop Hosted by the Foundation Fighting Blindness, 9/2020

On September 14–15, 2020, the Foundation Fighting Blindness convened a virtual workshop to discuss intraocular inflammation during viral vector-mediated gene therapy for inherited retinal diseases. The workshop's goals were to understand immune activation's nature and significance during ocular gene therapy, consider whether ocular inflammation limits gene therapy's potential, and identify knowledge gaps for future research. The event brought together a small group of experienced researchers in the field to present and discuss current data. Collectively, participants agreed that clinical, as well as subclinical, inflammation during ocular gene therapy is common. The severity of inflammation in both animal and clinical studies varied widely but is generally related to vector dose. Severe inflammation was associated with reduced gene therapy efficacy. However, the relationship between outcomes and subclinical inflammation, pre-existing antivector antibodies, or induced adaptive immune responses is still unclear. Uncertainties about the contribution of vector manufacturing issues to inflammation were also noted. Importantly, various immunosuppressive treatment protocols are being used, and this heterogeneity confounds conclusions about optimal strategies. Proposed near-term next steps include establishing an immunological consultant directory, establishing a data repository for pertinent animal and clinical data, and developing a larger meeting. Priority areas for future research include deeper understanding of immune activation during retinal diseases and during ocular gene therapy; better, harmonized application of animal models; and identifying best practices for managing gene therapy vector-related ocular inflammation. TRANSLATIONAL RELEVANCE: Subclinical or clinical inflammation often arises during ocular gene therapy with viral vectors. Understanding the biological bases and impacts on efficacy are important for clinical management and the improvement of future therapies.