Risk Mitigation of Immunogenicity: A Key to Personalized Retinal Gene Therapy

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.

Mannose-coupled AAV2: A second-generation AAV vector for increased retinal gene therapy efficiency

“…34 The inflammation described in dose-escalation studies reveals the higher titer cohort to be most at risk. 35 This dose dependence supports the need of new-generation rAAV vectors with an improved balance between efficacy and safety.…”

Gene Therapy for Retinal Degenerative Diseases: Progress, Challenges, and Future Directions

“… 14 , 29 , 56 Due to their tissue-specific tropisms, some of the most common AAV serotypes in use for retinal gene therapy include AAV2, AAV4, AAV5, and AAV8, as mentioned previously. 26 , 110 The use of recombinant or engineered vector capsids can further increase tissue-specific targeting by allowing more precise control over the various elements in a capsid, and vector modifications. Selection of cell-type-specific promoters, further refines targeting to the affected cell types.…”

“… 15 However, subretinal injections have not been associated with severe inflammation following treatment with AAV8, AAV2, or AAV5, increasing its appeal as a route of administration. 19 , 26 The use of corticosteroids is typical to reduce procedure-related inflammation and immune responses to the vector. 27 Targeted engineering of vector capsids may also alleviate inflammation and the use of robotic devices may alleviate the drift and error of human surgeons in the operating room.…”

“… 56 , 66 Increased non-ocular biodistribution of ranibizumab or bevacizumab have been observed with the intravitreal route causing systemic adverse events like ecchymosis, gastrointestinal and vaginal hemorrhage, hematoma, increased blood pressure, cerebrovascular accident, myocardial infarctions, iliac artery aneurysm, and death. 26 , 129 Intravitreal injection is also known to be more immunogenic than subretinal injection. 27 Adverum Biotechnologies terminated the development of ADVM-022, an intravitreal AAV-based aflibercept gene therapy for AMD and DME due to dose-limiting toxicity in multiple patients.…”

“…Although there have been safety issues observed in gene therapy trials outside the eyes, few serious adverse events directly related to recombinant AAV gene therapies have been reported in ocular gene therapy trials. 26 The combination of the procedure and the retinal gene therapy drug carries the potential for toxicity to the retina, which is already fragile due to the disease. 128 , 133 Adverse events include inflammatory responses, increases in intraocular pressure, loss of retinal layers, decrease in electroretinography (ERG) amplitudes, antidrug antibody (ADA) responses to vector, and toxicity in the photoreceptors and RPE layers.…”