Superior Retinal Gene Transfer and Biodistribution Profile of Subretinal Versus Intravitreal Delivery of AAV8 in Nonhuman Primates

Abstract

These data illustrate that subretinal application of rAAV8 leads to a more favorable biodistribution profile compared to intravitreal injections. Extraocular biodistribution is limited after subretinal delivery, while intravitreal injection leads to both greater and more persistent systemic exposure, evident in blood and lymphatic tissues. With the knowledge on the dynamics of shedding in a setting mimicking clinical application, guidelines can be developed to refine clinical trial protocols to reduce the risk for trial subjects and their environment.

Humoral Immune Response After Intravitreal But Not After Subretinal AAV8 in Primates and Patients

“…12,13 Part of the explanation for this enhanced humoral immune response might be the fact that the shedding and biodistribution of vector after intravitreal injections is considerably higher. 21 This study has certain limitations, including absence of absolute thresholds of clinical relevance for levels of antibodies against AAV8. Furthermore, there is no international standard for benchmarking across studies.…”

Suprachoroidal and Subretinal Injections of AAV Using Transscleral Microneedles for Retinal Gene Delivery in Nonhuman Primates

“…Intravitreal injections are easier to perform, but conventional AAV serotypes have limited access to the outer retina due to the ILM barrier, 26 and they may trigger more vitreous inflammation and host humoral immune responses. 31,32 Our study demonstrates a novel mode of transscleral viral vector delivery that can be performed in an office setting without surgery. By injecting the AAV through the scleral wall to the subretinal or suprachoroidal space, the technique provides more robust transgene expression than do intravitreal injections and different patterns of expression that may be suitable for different gene therapy applications.…”

“…At the same time, the extremely high blood flow through choroidal vessels-the highest of any tissue in the body 52 -likely limits the systemic exposure of viral vectors in the suprachoroidal space. In contrast, intravitreal AAVs exhibit greater biodistribution in systemic circulation akin to intravenous or intramuscular injections, 32 and they are associated with greater humoral and possibly cellular immune responses. 31,33,53 This is likely due to the greater trabecular outflow of AAV from the vitreous compared to the less efficient uveoscleral outflow through which suprachoroidal AAV could exit the eye.…”

“…Also, intravitreal AAV causes more intraocular inflammation and elicits a more potent humoral immune response than does subretinal administration. [31][32][33][34] The suprachoroidal space is the potential space located between the choroidal vasculature and the scleral wall of the eye. In humans, this layer is rarely detectable except in pathologic conditions when accumulation of suprachoroidal fluid becomes visible on ultrasonography, 35 although advances in spectral domain-optical coherence tomography (SD-OCT) allow the space to be visualized in some healthy eyes also.…”

Complement C3-targeted gene therapy restricts onset and progression of neurodegeneration in chronic mouse glaucoma

“…Intraretinal administration of AAV2.CR2-Crry did not increase mortality or occurrence of external infections compared to naïve mice (in over 50 treated mice; data not shown), suggesting no major systemic or off-target alterations in complement signaling, or concomitant general immunosuppression. However, it remains possible that there are extraocular effects since intravitreally delivered AAV2 has the potential to reach blood and lymphatic tissue, as demonstrated in other animal models 83 , and is able to induce innate and adaptive immune responses 84 . Locally, resident microglia are able to limit viral spread, and induce a potential neuroprotective effect secondary to this antiviral response 85 .…”