Intravitreal administration of adalimumab delays retinal degeneration in
            <i>rd10</i>
            mice

Olivares-González, Lorena; Velasco, Sheyla; Millán, José María; Rodrigo, Regina

doi:10.1096/fj.202000044rr

Cited by 26 publications

(20 citation statements)

References 103 publications

(132 reference statements)

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“…Few studies investigated the pharmacokinetics of IgGs in the murine eye, (e.g., adalimumab and conbercept). 33 , 42 Estimating an ocular half-life of 10 hours for golimumab based on the pharmacokinetics studies of conbercept in mice, 42 golimumab would be in excess to TNF-α for approximately seven days and should therefore be able to delay the observed phenotypes induced by AAV-TNF-α for seven days. Indeed, the single IVT injection of golimumab was sufficient to reduce retinal thickening, posterior synechiae, and the development of a fibrotic epiretinal membrane; it also partially rescued the impaired ERG response.…”

Section: Discussionmentioning

confidence: 99%

“…Similarly, in the rd10 mouse model of retinal degeneration, adalimumab reduced inflammasome activation and microglial activation and slowed down retinal degeneration. 33 Thus AAV-driven expression of human TNF-α mimics many aspects of human retinal diseases and may be used as a novel mouse model to further understand the pathophysiologic role of chronic TNF-α-related inflammation in the retina.…”

Section: Introductionmentioning

confidence: 99%

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Characterization and Validation of In Vitro and In Vivo Models to Investigate TNF-α-Induced Inflammation in Retinal Diseases

Weigelt

Zippel

Fuchs

et al. 2022

Trans. Vis. Sci. Tech.

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Purpose Inflammation is implicated in the etiology of diverse retinopathies including uveitis, age-related macular degeneration or diabetic retinopathy. Tumor necrosis factor alpha (TNF-α) is a well-known proinflammatory cytokine that is described as a biomarker for inflammation in diverse retinopathies and therefore emerged as an interesting target to treat inflammation in the eye by neutralizing anti-TNF-α antibodies. Methods Recently, we have demonstrated that Adeno-associated virus (AAV)–mediated expression of human TNF-α in the murine eye induces retinal inflammation including vasculitis and fibrosis, thereby mimicking human disease-relevant pathologies. In a proof-of-mechanism study, we now tested whether AAV-TNF-α induced pathologies can be reversed by neutralizing TNF-α antibody treatment. Results Strikingly, a single intravitreal injection of the TNF-α antibody golimumab reduced AAV-TNF-α–induced retinal inflammation and retinal thickening. Furthermore, AAV-TNF-α–mediated impaired retinal function was partially rescued by golimumab as revealed by electroretinography recordings. Finally, to study TNF-α-induced vasculitis in human in vitro cell culture assays, we established a monocyte-to-endothelium adhesion co-culture system. Indeed, also in vitro TNF-α induced monocyte adhesion to human retinal endothelial cells, which was prevented by golimumab. Conclusions Overall, our study describes valuable in vitro and in vivo approaches to study the function of TNF-α in retinal inflammation and demonstrated a preclinical proof-of-mechanism treatment with golimumab. Translational Relevance The AAV-based model expressing human TNF-α allows us to investigate TNF-α–driven pathologies supporting research in mechanisms of retinal inflammation.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Characterization and Validation of In Vitro and In Vivo Models to Investigate TNF-α-Induced Inflammation in Retinal Diseases

Weigelt

Zippel

Fuchs

et al. 2022

Trans. Vis. Sci. Tech.

View full text Add to dashboard Cite

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“…The increased expression of RIP1K/RIP3K molecules is linked with necroptosis in P23H-1 rhodopsin rats [ 23 ]. The high levels of NLRP3 inflammasome components (NLRP3, active caspase 1, and IL-1β) are associated with increased pyroptosis in murine and canine models of RP [ 23 , 28 , 29 ].…”

Section: Factors Contributing To Inflammation In Retinal Degenerative Diseasesmentioning

confidence: 99%

The Role of Inflammation in Retinal Neurodegeneration and Degenerative Diseases

Kaur

Singh

2021

IJMS

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Retinal neurodegeneration is predominantly reported as the apoptosis or impaired function of the photoreceptors. Retinal degeneration is a major causative factor of irreversible vision loss leading to blindness. In recent years, retinal degenerative diseases have been investigated and many genes and genetic defects have been elucidated by many of the causative factors. An enormous amount of research has been performed to determine the pathogenesis of retinal degenerative conditions and to formulate the treatment modalities that are the critical requirements in this current scenario. Encouraging results have been obtained using gene therapy. We provide a narrative review of the various studies performed to date on the role of inflammation in human retinal degenerative diseases such as age-related macular degeneration, inherited retinal dystrophies, retinitis pigmentosa, Stargardt macular dystrophy, and Leber congenital amaurosis. In addition, we have highlighted the pivotal role of various inflammatory mechanisms in the progress of retinal degeneration. This review also offers an assessment of various therapeutic approaches, including gene-therapies and stem-cell-based therapies, for degenerative retinal diseases.

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“…Indeed, TNF blockade with adalimumab, a monoclonal antibody, is clinically approved for the treatment of uveitis ( 124 , 125 ). In the rd10 model of RP, adalimumab slowed photoreceptor death when delivered either systemically or intravitreally ( 126 , 127 ). Similarly, anti-TNF therapies have been reported to suppress laser-induced CNV in mice ( 128 ), rats ( 129 ), and non-human primates ( 130 ).…”

Section: Strategies To Target Microglia In Eye Diseasementioning

confidence: 99%

Targeting Microglia to Treat Degenerative Eye Diseases

Wang

Cepko

2022

Front. Immunol.

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Microglia have been implicated in many degenerative eye disorders, including retinitis pigmentosa, age-related macular degeneration, glaucoma, diabetic retinopathy, uveitis, and retinal detachment. While the exact roles of microglia in these conditions are still being discovered, evidence from animal models suggests that they can modulate the course of disease. In this review, we highlight current strategies to target microglia in the eye and their potential as treatments for both rare and common ocular disorders. These approaches include depleting microglia with chemicals or radiation, reprogramming microglia using homeostatic signals or other small molecules, and inhibiting the downstream effects of microglia such as by blocking cytokine activity or phagocytosis. Finally, we describe areas of future research needed to fully exploit the therapeutic value of microglia in eye diseases.

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Intravitreal administration of adalimumab delays retinal degeneration in rd10 mice

Cited by 26 publications

References 103 publications

Characterization and Validation of In Vitro and In Vivo Models to Investigate TNF-α-Induced Inflammation in Retinal Diseases

Characterization and Validation of In Vitro and In Vivo Models to Investigate TNF-α-Induced Inflammation in Retinal Diseases

The Role of Inflammation in Retinal Neurodegeneration and Degenerative Diseases

Targeting Microglia to Treat Degenerative Eye Diseases

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