Lentiviral vector-mediated expression of C3 transferase attenuates retinal ischemia and reperfusion injury in rats

Tan, Junkai; Lan, Chunlin; Pang, Iok‐Hou; Luo, Xiaorong; Wu, Shen; Fan, Ning; Zhang, Jingxue; Wang, Ke; Liu, Xuyang

doi:10.1016/j.lfs.2021.119269

Cited by 8 publications

(6 citation statements)

References 42 publications

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“…On top of reduced visual functioning, retinal I/R was also found to be associated with decreased retinal thickness and GCL cell density, along with increased apoptosis [ 40 ]. In our study, these outcomes were reflected with increased TUNEL + , and decreased Fluoro-Gold + cells, which represented, respectively, apoptotic [ 41 ] and live ganglion cells.…”

Section: Discussionmentioning

confidence: 99%

Young Sca-1+ bone marrow stem cell-derived exosomes preserve visual function via the miR-150-5p/MEKK3/JNK/c-Jun pathway to reduce M1 microglial polarization

et al. 2023

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Background Polarization of microglia, the resident retinal immune cells, plays important roles in mediating both injury and repair responses post-retinal ischemia–reperfusion (I/R) injury, which is one of the main pathological mechanisms behind ganglion cell apoptosis. Aging could perturb microglial balances, resulting in lowered post-I/R retinal repair. Young bone marrow (BM) stem cell antigen 1-positive (Sca-1+) cells have been demonstrated to have higher reparative capabilities post-I/R retinal injury when transplanted into old mice, where they were able to home and differentiate into retinal microglia. Methods Exosomes were enriched from young Sca-1+ or Sca-1− cells, and injected into the vitreous humor of old mice post-retinal I/R. Bioinformatics analyses, including miRNA sequencing, was used to analyze exosome contents, which was confirmed by RT-qPCR. Western blot was then performed to examine expression levels of inflammatory factors and underlying signaling pathway proteins, while immunofluorescence staining was used to examine the extent of pro-inflammatory M1 microglial polarization. Fluoro-Gold labelling was then utilized to identify viable ganglion cells, while H&E staining was used to examine retinal morphology post-I/R and exosome treatment. Results Sca-1+ exosome-injected mice yielded better visual functional preservation and lowered inflammatory factors, compared to Sca-1−, at days 1, 3, and 7 days post-I/R. miRNA sequencing found that Sca-1+ exosomes had higher miR-150-5p levels, compared to Sca-1− exosomes, which was confirmed by RT-qPCR. Mechanistic analysis found that miR-150-5p from Sca-1+ exosomes repressed the mitogen-activated protein kinase kinase kinase 3 (MEKK3)/JNK/c-Jun axis, leading to IL-6 and TNF-α downregulation, and subsequently reduced microglial polarization, all of which contributes to reduced ganglion cell apoptosis and preservation of proper retinal morphology. Conclusion This study elucidates a potential new therapeutic approach for neuroprotection against I/R injury, via delivering miR-150-5p-enriched Sca-1+ exosomes, which targets the miR-150-5p/MEKK3/JNK/c-Jun axis, thereby serving as a cell-free remedy for treating retinal I/R injury and preserving visual functioning.

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Section: Discussionmentioning

confidence: 99%

Young Sca-1+ bone marrow stem cell-derived exosomes preserve visual function via the miR-150-5p/MEKK3/JNK/c-Jun pathway to reduce M1 microglial polarization

et al. 2023

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“…Therefore, the fundamental objectives of glaucoma treatment encompass regulating AqH production in the ciliary epithelium, augmenting AqH outflow through the trabecular meshwork, and fortifying RGCs resilience. Gene therapy for glaucoma naturally targets the ciliary epithelium [150][151][152], trabecular reticulum cells [153], and RGCs [154][155][156]. The development of gene therapy for glaucoma is predicated based on the ongoing investigation into its pathogenic etiology and disease pathways, with the identification of a novel gene target hinging upon its pivotal role in regulating RGC apoptosis or ON atrophy associated with glaucoma [157,158] The most common genetic disorder in optic neuropathy is Leber's hereditary optic neuropathy (LHON), which is characterized by progressive degeneration of RGCs [159].…”

Section: Gene Therapy For On Injurymentioning

confidence: 99%

The next‐generation therapies in ophthalmology for blindness worldwide

Xu,

Zhang,

Jiang

et al. 2024

Eye & ENT Research

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With the rapid and groundbreaking development in 21st century medicine on a global scale, new possibilities have emerged for addressing eye diseases, that can be blindness, and that conventional pharmaceuticals and surgical interventions have not hitherto been able to adequately treat. Gene enhancement/supplementation, gene editing, and stem cell therapies have now emerged as key subdisciplines. Here we discuss the current state and prospects of regenerative therapy in the field of ophthalmology, with a primary focus on diseases affecting the cornea, retina, and optic nerve. Our review summarizes the latest advances, challenges, and opportunities in these fields, as well as the potential applications and limitations of different strategies. The review also highlights the importance of interdisciplinary and collaborative innovation models for achieving breakthroughs in therapeutic development for sight‐loss diseases worldwide.

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“…From a neuroprotection angle, delivery of neurotrophin genes and its receptor protein to damaged or dying RGCs in order to preserve them and reduce vision loss also appears very promising for preserving vision in glaucoma suspects and in patients suffering from POAG/NTG [ 74 ]. More recently, self-complementary AAV2 encoding a complement C3 protein, a destructive RGC attack and cell death-causing element, intravitreally delivered in rats protected the RGCs when the animals were subjected to ischemia/reperfusion-induced retinal injury [ 89 ]. Similarly, delivery of gene therapy for the X-linked inhibitor of apoptosis [ 90 ] and BCLX, the endogenous antagonist of BAX (a damaging transcription factor that causes apoptosis) [ 91 ], afforded protection and preservation of RGC cell structure and function in two different rodent models of glaucoma.…”

Section: Poag and Gene Therapymentioning

confidence: 99%

Elevated Intraocular Pressure and Glaucomatous Optic Neuropathy: Genes to Disease Mechanisms, Therapeutic Drugs, and Gene Therapies

Sharif

2023

Pharmaceuticals

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This review article focuses on the pathogenesis of and genetic defects linked with chronic ocular hypertension (cOHT) and glaucoma. The latter ocular disease constitutes a group of ocular degenerative diseases whose hallmark features are damage to the optic nerve, apoptotic demise of retinal ganglion cells, disturbances within the brain regions involved in visual perception and considerable visual impairment that can lead to blindness. Even though a number of pharmaceuticals, surgical and device-based treatments already exist addressing cOHT associated with the most prevalent of the glaucoma types, primary open-angle glaucoma (POAG), they can be improved upon in terms of superior efficacy with reduced side-effects and with longer duration of activity. The linkage of disease pathology to certain genes via genome-wide associated studies are illuminating new approaches to finding novel treatment options for the aforementioned ocular disorders. Gene replacement, gene editing via CRISPR-Cas9, and the use of optogenetic technologies may replace traditional drug-based therapies and/or they may augment existing therapeutics for the treatment of cOHT and POAG in the future.

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Lentiviral vector-mediated expression of C3 transferase attenuates retinal ischemia and reperfusion injury in rats

Cited by 8 publications

References 42 publications

Young Sca-1+ bone marrow stem cell-derived exosomes preserve visual function via the miR-150-5p/MEKK3/JNK/c-Jun pathway to reduce M1 microglial polarization

Young Sca-1+ bone marrow stem cell-derived exosomes preserve visual function via the miR-150-5p/MEKK3/JNK/c-Jun pathway to reduce M1 microglial polarization

The next‐generation therapies in ophthalmology for blindness worldwide

Elevated Intraocular Pressure and Glaucomatous Optic Neuropathy: Genes to Disease Mechanisms, Therapeutic Drugs, and Gene Therapies

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