Abstract
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 RelevanceSubclinical 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.
Highlights
Gene therapies predominantly use viral vectors for in vivo delivery of genes to augment or repair dysfunctional inherited genes
the degree of inflammation is correlated with dose
more than 300 genes and loci have been implicated in causing inherited retinal diseases
Summary
Gene therapies predominantly use viral vectors for in vivo delivery of genes to augment or repair dysfunctional inherited genes. More than 300 genes and loci have been implicated in causing inherited retinal diseases (IRDs), which are mostly monogenic, with varying inheritance patterns. Many of these single-gene defects may be amenable to gene therapy strategies, and efforts to develop gene-based treatments have been underway for more than 30 years. The approval of Kymriah, which uses ex vivo delivery of a chimeric antigen receptor via a lentiviral vector (Oxford BioMedica, Oxford, UK/Novartis, Basel, Switzerland) to patient T cells, validated the power of the approach. Subretinal administration of Luxturna delivers wildtype cDNA encoding RPE65 directly to the subretinal region of diseased eyes, thereby improving functional vision
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