scAAV2-Mediated C3 Transferase Gene Therapy in a Rat Model with Retinal Ischemia/Reperfusion Injuries

Tan, Junkai; Zhang, Xiaoguang; Li, Danli; Wang, Yun; Zhang, Daren; Wang, Xizhen; Tian, Wenhong; Dong, Xiaoyan; Zhou, Liang; Zhu, Xuejun; Liu, Xuyang; Fan, Ning

doi:10.1016/j.omtm.2020.04.014

Cited by 10 publications

(10 citation statements)

References 49 publications

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“…Given impaired OPs amplitude and remarkably cell loss in GCL were observed in Yap1 ChxKO mice, we next set out to investigate the GCL pathologies. To directly visualize the cell content in GCL of control and Yap1 ChxKO mice, wholemount retinas from 10‐month‐old mice were immunostained with a specific neuronal marker NeuN, which labels cells resided predominantly in the GCL (Tan et al, 2020). To this end, we imaged four equivalent prescribed areas each located 1 mm from the ON head (nasal, temporal, ventral, and dorsal) per retina and quantified the cell density of GCL by determining NeuN‐positive cells per unit area.…”

Section: Resultsmentioning

confidence: 99%

“…Immunostaining using RBC specific marker PKCα revealed the malformation and loss of RBCs in Yap1 ChxKO retina compare to that of controls (Figure 5a). The mean numbers of PKCα-positive cells in the control and Yap1 ChxKO mice were 19.8 ± 0.8 and 12.9 ± 1. were immunostained with a specific neuronal marker NeuN, which labels cells resided predominantly in the GCL (Tan et al, 2020). To this end, we imaged four equivalent prescribed areas each located 1 mm from the ON head (nasal, temporal, ventral, and dorsal) per retina and quantified the cell density of GCL by determining NeuNpositive cells per unit area.…”

Section: Yap Maintains the Survival Of Multiple Cell Types In Inlmentioning

confidence: 99%

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Specific ablation of Hippo signalling component Yap1 in retinal progenitors and Müller cells results in late onset retinal degeneration

Yang

Jiang

Xiao

et al. 2022

Journal Cellular Physiology

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Yes-associated protein (YAP) is a major component of the Hippo pathway involved in development, growth, repair and homeostasis. Nonsense YAP1 mutations in humans result in autosomal dominant coloboma. Here, we generated a conditional knockout mouse model in which Yap1 was specifically deleted in embryonic retinal progenitor cells (RPCs) and in mature Müller cells using a Chx10-Cre driver. Our data demonstrated that the conditional ablation of Yap1 in embryonic RPCs does not prevent normal retinal development and caused no gross changes in retinal structure during embryonic and early postnatal life. Nevertheless, Yap1 deficient in retinal Müller cells in adult mice leads to impaired visual responses and extensive late-onset retinal degeneration, characterized by reduced cell number in all retinal layers. Immunofluorescence data further revealed the degeneration and death of rod and cone photoreceptors, bipolar cells, horizontal cells, amacrine cells and ganglion cells to varying degrees in aged knockout mice. Moreover, alteration of glial homeostasis and reactive gliosis were also observed. Finally, cell proliferation and TUNEL assay revealed that the broad retinal degeneration is mainly caused by enhanced apoptosis in late period. Together, this work uncovers that YAP is essential for the normal vision and retinal maintenance, highlighting the crucial role of YAP in retinal function and homeostasis.

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Section: Resultsmentioning

confidence: 99%

Section: Yap Maintains the Survival Of Multiple Cell Types In Inlmentioning

confidence: 99%

Specific ablation of Hippo signalling component Yap1 in retinal progenitors and Müller cells results in late onset retinal degeneration

Yang

Jiang

Xiao

et al. 2022

Journal Cellular Physiology

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“…Exoenzyme C3 transferase (C3) can inactivate Rho GTPases, which are involved in cellular processes such as the regulation of cell proliferation and apoptosis [ 21 ]. C3 can protect RGCs from NMDA induced excitotoxicity in rats [ 56 ].…”

Section: Resultsmentioning

confidence: 99%

“…C3 can protect RGCs from NMDA induced excitotoxicity in rats [ 56 ]. One group evaluated a self-complementary AAV encoding C3 (scAAV-C3) in a I/R injury model in rats [ 21 ]. The I/R was induced through the temporary elevation of IOP to 110 mmHg for 90 min with saline.…”

Section: Resultsmentioning

confidence: 99%

Use of Gene Therapy in Retinal Ganglion Cell Neuroprotection: Current Concepts and Future Directions

Rhee

Shih

2021

Biomolecules

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We systematically reviewed published translational research on gene-based therapy for retinal ganglion cell (RGC) neuroprotection. A search was conducted on Entrez PubMed on 23 December 2020 using the keywords “gene therapy”, “retinal ganglion cell” and “neuroprotection. The initial search yielded 82 relevant articles. After restricting publications to those with full text available and in the English language, and then curating for only original articles on gene-based therapy, the final yield was 18 relevant articles. From the 18 papers, 17 of the papers utilized an adeno-associated viral (AAV) vector for gene therapy encoding specific genes of interest. Specifically, six of the studies utilized an AAV vector encoding brain-derived neurotrophic factor (BDNF), two of the studies utilized an AAV vector encoding erythropoietin (EPO), the remaining 10 papers utilized AAV vectors encoding different genes and one microRNA study. Although the literature shows promising results in both in vivo and in vitro models, there is still a significant way to go before gene-based therapy for RGC neuroprotection can proceed to clinical trials. Namely, the models of injury in many of the studies were more acute in nature, unlike the more progressive and neurodegenerative pathophysiology of diseases, such as glaucoma. The regulation of gene expression is also highly unexplored despite the use of AAV vectors in the majority of the studies reviewed. It is also expected that with the successful launch of messenger ribonucleic acid (mRNA)-based vaccinations in 2020, we will see a shift towards this technology for gene-based therapy in glaucoma neuroprotection.

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“…Given the significance of aqueous humour outflow regulation on glaucoma pathogenesis, additional strategies have explored the expression of molecules involved in this process as potential gene therapies. Tan et al assessed the efficacy of overexpression of C3 exoenzyme transferase (C3), a molecule which disrupts the actin cytoskeleton and cellular adhesion in TM cells by inactivating Rho, whose signalling pathway is crucial in IOP regulation ( Refs 64,65). Using a self-complementary AAV2 (scAAV2), intracameral C3 expression lowered IOP in healthy monkeys and mice despite some adverse reactions (Refs 64, 66).…”

Section: Aav-mediated Gene Therapies Targeting the Aqueous Humour Out...mentioning

confidence: 99%

AAV-mediated gene therapies for glaucoma and uveitis: are we there yet?

Castro,

Steel,

Layton

2024

Expert Rev. Mol. Med.

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Glaucoma and uveitis are non-vascular ocular diseases which are among the leading causes of blindness and visual loss. These conditions have distinct characteristics and mechanisms but share a multifactorial and complex nature, making their management challenging and burdensome for patients and clinicians. Furthermore, the lack of symptoms in the early stages of glaucoma and the diverse aetiology of uveitis hinder timely and accurate diagnoses, which are a cause of poor visual outcomes under both conditions. Although current treatment is effective in most cases, it is often associated with low patient adherence and adverse events, which directly impact the overall therapeutic success. Therefore, long-lasting alternatives with improved safety and efficacy are needed. Gene therapy, particularly utilising adeno-associated virus (AAV) vectors, has emerged as a promising approach to address unmet needs in these diseases. Engineered capsids with enhanced tropism and lower immunogenicity have been proposed, along with constructs designed for targeted and controlled expression. Additionally, several pathways implicated in the pathogenesis of these conditions have been targeted with single or multigene expression cassettes, gene editing and silencing approaches. This review discusses strategies employed in AAV-based gene therapies for glaucoma and non-infectious uveitis and provides an overview of current progress and future directions.

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scAAV2-Mediated C3 Transferase Gene Therapy in a Rat Model with Retinal Ischemia/Reperfusion Injuries

Cited by 10 publications

References 49 publications

Specific ablation of Hippo signalling component Yap1 in retinal progenitors and Müller cells results in late onset retinal degeneration

Specific ablation of Hippo signalling component Yap1 in retinal progenitors and Müller cells results in late onset retinal degeneration

Use of Gene Therapy in Retinal Ganglion Cell Neuroprotection: Current Concepts and Future Directions

AAV-mediated gene therapies for glaucoma and uveitis: are we there yet?

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