Abstract
Gene therapy (GT) for ocular disorders has advanced the most among adeno-associated virus (AAV)-mediated therapies, with one product already approved in the market. The bank of retinal gene mutations carefully compiled over 30 years, the small retinal surface that does not require high clinical vector stocks, and the relatively immune-privileged environment of the eye explain such success. However, adverse effects due to AAV-delivery, though rare in the retina have led to the interruption of clinical trials. Risk mitigation, as the key to safe and efficient GT, has become the focus of ‘bedside-back-to-bench’ studies. Herein, we overview the inflammatory adverse events described in retinal GT trials and analyze which components of the retinal immunological environment might be the most involved in these immune responses, with a focus on the innate immune system composed of microglial surveillance. We consider the factors that can influence inflammation in the retina after GT such as viral sensors in the retinal tissue and CpG content in promoters or transgene sequences. Finally, we consider options to reduce the immunological risk, including dose, modified capsids or exclusion criteria for clinical trials. A better understanding and mitigation of immune risk factors inducing host immunity in AAV-mediated retinal GT is the key to achieving safe and efficient GT.
Highlights
Recombinant adeno-associated virus-derived vectors have been the technological key enabling in vivo gene transfer in the last decade, with hundreds of clinical trials underway
The criterion may in some cases depend on the nature of the Recombinant adeno-associated virus (rAAV) treatment; serology of subjects regarding NAbs is a recurrent criterion for patient exclusion in ocular Gene therapy (GT) trials as high doses of vectors in patients with preexisting immunity against associated virus (AAV) may leave them at risk
As AAV GT has moved from its development phase to clinical application, efforts to “derisk” the vector as much as possible have accelerated
Summary
Recombinant adeno-associated virus (rAAV)-derived vectors have been the technological key enabling in vivo gene transfer in the last decade, with hundreds of clinical trials underway. An active local or peripheral tolerance to prevent runaway immune responses can be induced in some cases through the conversion of T cell to regulatory T cells (Treg) or the apoptosis of infiltrated effector T cells by inhibitory molecules expressed on the retinal pigmented epithelium (RPE) or resident stromal cells [9,10,11]. This immune suppressive environment of the eye is only relative. We consider strategies to mitigate the immunological risk of rAAV-based ocular new treatments
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
