Transduction Pattern of AAVs in the Trabecular Meshwork and Anterior-Segment Structures in a Rat Model of Ocular Hypertension

Lee, Si Hyung; Sim, Kyeong Sun; Kim, Chan Yun; Park, Tae Kwann

doi:10.1016/j.omtm.2019.06.009

Cited by 18 publications

(15 citation statements)

References 49 publications

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“…Similar to our results, intracameral delivery of the scAAV2 vectors (containing cytomegalovirus [CMV] promoter in most of these studies) transduced not only the TM but also the CE and iris in live animals, including mice, 36 rats, 13 , 22 , 36 , 37 sheep, 38 and monkeys, 13 without inducing an inflammatory response and other abnormalities. Gruenert et al 39 .…”

Section: Discussionsupporting

confidence: 88%

C3 Transferase-Expressing scAAV2 Transduces Ocular Anterior Segment Tissues and Lowers Intraocular Pressure in Mouse and Monkey

Tan

Wang

Cai

et al. 2020

Molecular Therapy - Methods & Clinical Development

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Glaucoma is a lifelong disease with elevated intraocular pressure (IOP) as the main risk factor, and reduction of IOP remains the major treatment for this disease. However, current IOP-lowering therapies are far from being satisfactory. We have demonstrated that the lentivirus-mediated exoenzyme C3 transferase (C3) expression in rat and monkey eyes induced relatively long-term IOP reduction. We now show that intracameral injection of self-complementary AAV2 containing a C3 gene into mouse and monkey eyes resulted in morphological changes in trabecular meshwork and IOP reduction. The vector-transduced corneal endothelium and the C3 transgene expression, not vector itself, induced corneal edema as a result of actin-associated endothelial barrier disruption. There was a positive (quadratic) correlation between measured IOP and grade of corneal edema. This is the first report of using an AAV to transduce the trabecular meshwork of monkeys with a gene capable of altering cellular structure and physiology, indicating a potential gene therapy for glaucoma.

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Section: Discussionsupporting

confidence: 88%

C3 Transferase-Expressing scAAV2 Transduces Ocular Anterior Segment Tissues and Lowers Intraocular Pressure in Mouse and Monkey

Tan

Wang

Cai

et al. 2020

Molecular Therapy - Methods & Clinical Development

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“…One potential approach to long-term drug delivery is the use of gene therapy, which is being developed as a specific targeted therapy for multiple genetic diseases and has been explored in detail for ocular diseases including glaucoma and inherited retinal diseases, including Luxturna, the first gene therapy biologic to be granted market approval 18–20 . Gene therapy based on adeno-associated virus (AAV) vectors is currently the most promising approach with a convincing safety profile in hundreds of treated patients.…”

Section: Introductionmentioning

confidence: 99%

“…AAV serotypes 1–12 have been described to have tropism for different ocular cell types and target tissues, presumably due to variations in capsid and host cell receptor affinities, nuclear trafficking, and/or uncoating 22–24 . Although there are numerous serotypes, AAV serotype 8 (AAV8) has been previously shown to effectively transduce the ocular uveal tissue 20–22,25,26 .…”

Section: Introductionmentioning

confidence: 99%

AAV-mediated expression of HLA-G1/5 reduces severity of experimental autoimmune uveitis

Crabtree

Song

Llanga

et al. 2019

Sci Rep

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Non-infectious uveitis (NIU) is an intractable, recurrent, and painful disease that is a common cause of vision loss. Available treatments of NIU, such as the use of topical corticosteroids, are non-specific and have serious side effects which limits them to short-term use; however, NIU requires long-term treatment to prevent vision loss. Therefore, a single dose therapeutic that mediates long-term immunosuppression with minimal side effects is desirable. In order to develop an effective long-term therapy for NIU, an adeno-associated virus (AAV) gene therapy approach was used to exploit a natural immune tolerance mechanism induced by the human leukocyte antigen G (HLA-G). To mimic the prevention of NIU, naïve Lewis rats received a single intravitreal injection of AAV particles harboring codon-optimized cDNAs encoding HLA-G1 and HLA-G5 isoforms one week prior to the induction of experimental autoimmune uveitis (EAU). AAV-mediated expression of the HLA-G-1 and -5 transgenes in the targeted ocular tissues following a single intravitreal injection of AAV-HLA-G1/5 significantly decreased clinical and histopathological inflammation scores compared to untreated EAU eyes (p < 0.04). Thus, localized ocular gene delivery of AAV-HLA-G1/5 may reduce the off-target risks and establish a long-term immunosuppressive effect that would serve as an effective and novel therapeutic strategy for NIU, with the potential for applications to additional ocular immune-mediated diseases.

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“…Synthetically developed AAV, Anc80L65, has been shown to transduce the anterior segment, including the TM, the corneal stroma, and endothelial cells. Self-complementary AAV2, scAAV5, and scAAV8 have been shown to transduce the ciliary body, the iris, and the corneal endothelium of ocular hypertensive eyes [ 26 ]. The intracameral injection might be an inefficient method because of the rapid turnover of aqueous humor and the short contact time with ocular tissues [ 21 ].…”

Section: Routes Of Administration For Ocular Gene Therapymentioning

confidence: 99%

Viral-Vector-Delivered Anti-Angiogenic Therapies to the Eye

et al. 2021

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Pathological vessel growth harms vision and may finally lead to vision loss. Anti-angiogenic gene therapy with viral vectors for ocular neovascularization has shown great promise in preclinical studies. Most of the studies have been conducted with different adeno-associated serotype vectors. In addition, adeno- and lentivirus vectors have been used. Therapy has been targeted towards blocking vascular endothelial growth factors or other pro-angiogenic factors. Clinical trials of intraocular gene therapy for neovascularization have shown the treatment to be safe without severe adverse events or systemic effects. Nevertheless, clinical studies have not proceeded further than Phase 2 trials.

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Transduction Pattern of AAVs in the Trabecular Meshwork and Anterior-Segment Structures in a Rat Model of Ocular Hypertension

Cited by 18 publications

References 49 publications

C3 Transferase-Expressing scAAV2 Transduces Ocular Anterior Segment Tissues and Lowers Intraocular Pressure in Mouse and Monkey

C3 Transferase-Expressing scAAV2 Transduces Ocular Anterior Segment Tissues and Lowers Intraocular Pressure in Mouse and Monkey

AAV-mediated expression of HLA-G1/5 reduces severity of experimental autoimmune uveitis

Viral-Vector-Delivered Anti-Angiogenic Therapies to the Eye

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