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

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 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.

Ocular Gene Therapy: A Literature Review with Special Focus on Immune and Inflammatory Responses

“…This was true in both subretinal and intravitreal deliveries, although the same viral dose induced lower immune responses when delivered via the subretinal route. 91 , 105–107 For example, Cukras et al found a dose-dependent response of ocular inflammation. 41 They evaluated the safety of AAV8 as the vector for delivery of RS1 gene in patients with XLRS caused by RS1 gene mutations in a phase I/II an open-label clinical trial.…”

Immunogenicity of Novel AAV Capsids for Retinal Gene Therapy

“…Although the eye is an immune-privileged organ, ocular gene therapy is often hampered by inflammation in the patient’s eyes, especially after intravitreal application of AAV vectors [ 26 ]. Due to the presence of less vector spreading and the immune privilege of the subretinal space, subretinal injection of AAV vectors appears to be less immunogenic, but carries the risk of adverse effects because retinal detachment is required to enable transduction of retinal pigment epithelium or the photoreceptors [ 26 ]. In order to overcome this limitation, next-generation AAV vectors with an enhanced tropism that transduce target cells in the outer retina (e.g., rod or cone photoreceptors) after intravitreal injection are currently being developed [ 15 ].…”

“…Moreover, in the healthy eye serum antibodies are excluded from the inner compartments (e.g., retina) by the blood–eye barriers. Therefore, neutralizing antibodies might appear to be a lesser problem for ocular than for intravenously applied gene therapy [ 26 ]. However, under pathologic conditions leading to permeability or even breakdown of the blood–ocular barrier, the situation could be different.…”

Advances in Ophthalmic Optogenetics: Approaches and Applications

“…One general concern for AAV vectors is that pre-existing immunity and subsequent induced adaptive immunity following vector administration can significantly reduce retinal gene expression, as shown in pre-clinical studies [ 82 ]. Furthermore, there is growing appreciation for the risk of gene therapy associated uveitis following AAV administration, which appears to be related to the vector dose and route of administration [ 83 , 84 ]. However, optogenetic clinical trials thus far have demonstrated that intravitreal delivery of AAV-based vectors is mostly safe and well-tolerated [ 8 ].…”