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

Reichel, Felix Friedrich; Peters, Tobias; Wilhelm, Barbara; Biel, Martin; Ueffing, Marius; Wissinger, Bernd; Bartz‐Schmidt, Karl Ulrich; Klein, Reinhild; Michalakis, Stylianos; Fischer, Manuel

doi:10.1167/iovs.17-22494

Cited by 69 publications

(62 citation statements)

References 21 publications

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“…In contrast, the animal that received intravitreal AAV8 demonstrated a more significant elevation in NAb titers at 1 month ( Figures 6B and 6C), consistent with the response to intravitreal AAV8 in previous primate studies. 33,34 As predicted, the animal that received the lower dose of AAV8 in both eyes (7 Â 10 11 vg/eye) exhibited a milder NAb response. NAbs were not detectable in aqueous samples of any study animals (Figure 6D).…”

Section: Humoral Immune Responses After Different Modes Of Aav8 Deliverysupporting

confidence: 61%

“…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. Hence, although AAV sequestration in the suprachoroidal space may lead to greater local inflammation, the higher systemic exposure of intravitreal AAV triggers a stronger systemic immune response, which may reduce the efficacy and durability of transgene expression.…”

Section: Discussionmentioning

confidence: 99%

“…This corresponds to Goldmann-Witmer (G-W) ratio below 4 in all eyes, which indicates minimal intraocular inflammation as detected from the aqueous after all modes of AAV injection in our study. Since past studies did not show a significant NAb response after subretinal AAV8 alone, 33,34 and because the animals that received suprachoroidal and subretinal injection in fellow eyes (rhesus 03 and rhesus 04) showed a similar NAb response as animals that received bilateral suprachoroidal injections, the humoral immune response in these animals likely arose primarily from the suprachoroidal AAV8.…”

Section: Humoral Immune Responses After Different Modes Of Aav8 Deliverymentioning

confidence: 94%

“…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.…”

Section: Introductionmentioning

confidence: 99%

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

Yiu

Chung

Mollhoff

et al. 2020

Molecular Therapy - Methods & Clinical Development

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Retinal gene therapy using adeno-associated viruses (AAVs) is constrained by the mode of viral vector delivery. Intravitreal AAV injections are impeded by the internal limiting membrane barrier, while subretinal injections require invasive surgery and produce a limited region of therapeutic effect. In this study, we introduce a novel mode of ocular gene delivery in rhesus macaques using transscleral microneedles to inject AAV8 into the subretinal or suprachoroidal space, a potential space between the choroid and scleral wall of the eye. Using in vivo imaging, we found that suprachoroidal AAV8 produces diffuse, peripheral expression in retinal pigment epithelial (RPE) cells, but it elicited local infiltration of inflammatory cells. Transscleral subretinal injection of AAV8 using microneedles leads to focal gene expression with transduction of RPE and photoreceptors, and minimal intraocular inflammation. In comparison, intravitreal AAV8 shows minimal transduction of retinal cells, but elicits greater systemic humoral immune responses. Our study introduces a novel mode of transscleral viral delivery that can be performed without vitreoretinal surgery, with focal or diffuse transgene expression patterns suitable for different applications. The decoupling of local and systemic immune responses reveals important insights into the immunological consequences of AAV delivery to different ocular compartments surrounding the bloodretinal barrier.

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Section: Humoral Immune Responses After Different Modes Of Aav8 Deliverysupporting

confidence: 61%

Section: Discussionmentioning

confidence: 99%

Section: Humoral Immune Responses After Different Modes Of Aav8 Deliverymentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

Yiu

Chung

Mollhoff

et al. 2020

Molecular Therapy - Methods & Clinical Development

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“…113 Anti-capsid antibodies have been detected even after AAV injections into regions that are considered to be immune privileged, such as the brain 92 or intravitreal space. 114,115 Nevertheless, the development of immunosuppressive treatments has protected against AAV capsid immunity. [116][117][118] Indeed, long-term transgene expression has been observed after systemic AAV administration of genes, such as myotubularin 119,120 and microdystrophin, 121 promoting AAV-based treatments for patients with X-linked myotubular myopathy and Duchenne muscular dystrophy, respectively.…”

Section: Discussionmentioning

confidence: 99%

Intrathymic adeno-associated virus gene transfer rapidly restores thymic function and long-term persistence of gene-corrected T cells

Pouzolles

Machado

Guilbaud

et al. 2020

Journal of Allergy and Clinical Immunology

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Background: Patients with T-cell immunodeficiencies are generally treated with allogeneic hematopoietic stem cell transplantation, but alternatives are needed for patients without matched donors. An innovative intrathymic gene therapy approach that directly targets the thymus might improve outcomes. Objective: We sought to determine the efficacy of intrathymic adeno-associated virus (AAV) serotypes to transduce thymocyte subsets and correct the T-cell immunodeficiency in a zetaassociated protein of 70 kDa (ZAP-70)-deficient murine model. Methods: AAV serotypes were injected intrathymically into wild-type mice, and gene transfer efficiency was monitored. ZAP-70 2/2 mice were intrathymically injected with an AAV8 vector harboring the ZAP70 gene. Thymus structure, immunophenotyping, T-cell receptor clonotypes, T-cell function, immune responses to transgenes and autoantibodies, vector copy number, and integration were evaluated. Results: AAV8, AAV9, and AAV10 serotypes all transduced thymocyte subsets after in situ gene transfer, with transduction of up to 5% of cells. Intrathymic injection of an AAV8-ZAP-70 vector into ZAP-70 2/2 mice resulted in a rapid thymocyte differentiation associated with the development of a thymic medulla. Strikingly, medullary thymic epithelial cells expressing the autoimmune regulator were detected within 10 days of gene transfer, correlating with the presence of functional effector and regulatory T-cell subsets with diverse T-cell receptor clonotypes in the periphery. Although thymocyte reconstitution was transient, gene-corrected peripheral T cells harboring approximately 1 AAV genome per cell persisted for more than 40 weeks, and AAV vector integration was detected. Conclusions: Intrathymic AAV-transduced progenitors promote a rapid restoration of the thymic architecture, with a single wave of thymopoiesis generating long-term peripheral T-cell function.

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Emerging Therapeutic Modalities for Diabetic Retinopathy

Uddin

Jayagopal

2020

Topics in Medicinal Chemistry

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

Cited by 69 publications

References 21 publications

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

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

Intrathymic adeno-associated virus gene transfer rapidly restores thymic function and long-term persistence of gene-corrected T cells

Emerging Therapeutic Modalities for Diabetic Retinopathy

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