Progress on ocular siRNA gene‐silencing therapy and drug delivery systems

Jiang, Jinjin; Zhang, Xinru; Tang, Yue; Li, Shuhan; Chen, Jing

doi:10.1111/fcp.12561

Cited by 34 publications

(40 citation statements)

References 121 publications

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“…Gene silencing by small interfering RNA (siRNA) is one of the most promising techniques to translate the fundamental mechanism of RNAi to clinical applications. RNAibased therapies using siRNAs to silence aberrant genes are currently being developed for various human diseases, including ocular disorders [2,3]. To date, there are several naked or chemically modified siRNA drugs for the treatment of eye diseases completing Phase II clinical trials, e.g., Tivanisiran for dry eye [3], AGN211745 and PF-045233655 for AMD and QPI-1007 and Bamosiran for glaucoma and ocular hypertension [2], by targeting and silencing different aberrant proteins.…”

Section: Discussionmentioning

confidence: 99%

“…Advances in understanding RNA interference (RNAi)-based signaling pathways have opened up new therapeutic perspectives for a wide range of ocular disorders. The use of small interfering RNA (siRNA)-induced gene silencing has great potential in the treatment of chronic eye diseases such as some forms of retinitis pigmentosa (RP), age-related macular degeneration (AMD), diabetic retinopathy and glaucoma, which are associated with aberrant activities of specific proteins [1][2][3]. The eye is indeed an attractive target organ for RNA-based therapies.…”

Section: Introductionmentioning

confidence: 99%

“…Virus-based vectors are presently the most encouraging option for siRNA delivery in treating retinal disease [16,17]. Nonetheless, viral vectors require invasive subretinal injections that include topical retinal detachment, and their potential risk regarding immunogenicity, readministration, large-scale production, and high manufacturing costs make these methods cumbersome [2]. Consequently, there is a clear need for an effective, safe, and noninvasive method of administering siRNAs that can ascertain its effective delivery into deeper retinal layers.…”

Section: Introductionmentioning

confidence: 99%

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Efficient Ocular Delivery of VCP siRNA via Reverse Magnetofection in RHO P23H Rodent Retina Explants

et al. 2021

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The use of synthetic RNA for research purposes as well as RNA-based therapy and vaccination has gained increasing importance. Given the anatomical seclusion of the eye, small interfering RNA (siRNA)-induced gene silencing bears great potential for targeted reduction of pathological gene expression that may allow rational treatment of chronic eye diseases in the future. However, there is yet an unmet need for techniques providing safe and efficient siRNA delivery to the retina. We used magnetic nanoparticles (MNPs) and magnetic force (Reverse Magnetofection) to deliver siRNA/MNP complexes into retinal explant tissue, targeting valosin-containing protein (VCP) previously established as a potential therapeutic target for autosomal dominant retinitis pigmentosa (adRP). Safe and efficient delivery of VCP siRNA was achieved into all retinal cell layers of retinal explants from the RHO P23H rat, a rodent model for adRP. No toxicity or microglial activation was observed. VCP silencing led to a significant decrease of retinal degeneration. Reverse Magnetofection thus offers an effective method to deliver siRNA into retinal tissue. Used in combination with retinal organotypic explants, it can provide an efficient and reliable preclinical test platform of RNA-based therapy approaches for ocular diseases.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Efficient Ocular Delivery of VCP siRNA via Reverse Magnetofection in RHO P23H Rodent Retina Explants

et al. 2021

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“…77 As may be expected, dosing the eye does not induce significant systemic effects. 44,[78][79][80][81] Many RNAi-based therapies are in various stages of clinical trials for multiple indications, with the use of modified siRNA conjugates becoming a dominant therapeutic modality. 82 Other RNAi-based therapies for hepatitis C and various cancers are also in clinical trials.…”

Section: Discussionmentioning

confidence: 99%

“…Given the accessibility of the eye, treatment of ocular disease with siRNAs is an important new modality. 43,44 To understand the different functions of USP10 in wound healing, we have performed an in vivo knockdown using self-deliverable RNAi technology (sdRNAi). This approach is based on the use of fully modified asymmetric siRNA conjugated to cholesterol.…”

Section: Introductionmentioning

confidence: 99%

USP10 Targeted Self-Deliverable siRNA to Prevent Scarring in the Cornea

Boumil

Castro

Phillips

et al. 2020

Molecular Therapy - Nucleic Acids

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Ocular scarring after surgery, trauma, or infection leads to vision loss. The transparent cornea is an excellent model system to test anti-scarring therapies. Cholesterol-conjugated fully modified asymmetric small interfering RNAs (siRNAs) (selfdeliverable siRNAs [sdRNAs]) are a novel modality for in vivo gene knockdown, transfecting cells and tissues without any additional formulations. Myofibroblasts are a main contributor to scarring and fibrosis. a v integrins play a central role in myofibroblast pathological adhesion, overcontraction, and transforming growth factor b (TGF-b) activation. Previously, we demonstrated that a v integrins are protected from intracellular degradation after wounding by upregulation of the deubiquitinase (DUB) ubiquitin-specific protease 10 (USP10), leading to integrin cell surface accumulation. In this study, we tested whether knockdown of USP10 with a USP10-targeting sdRNA (termed US09) will reduce scarring after wounding a rabbit cornea in vivo. The wounded corneal stroma was treated once with US09 or non-targeting control (NTC) sdRNA. At 6 weeks US09 treatment resulted in faster wound closure, limited scarring, and suppression of fibrotic markers and immune response. Specifically, fibronectin-extra domain A (EDA), collagen III, and a-smooth muscle actin (p < 0.05), CD45 + cell infiltration (p < 0.01), and apoptosis at 24 (p < 0.01) and 48 h (p < 0.05) were reduced post-wounding. Corneal thickness and cell proliferation were restored to unwounded parameters. Targeting the DUB, USP10 is a novel strategy to reduce scarring. This study indicates that ubiquitin-mediated pathways should be considered in the pathogenesis of fibrotic healing.

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siRNA‐based nanotherapeutics as emerging modalities for immune‐mediated diseases: A preliminary review

Sargazi

Arshad

Ghamari

et al. 2022

Cell Biology International

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Immune-mediated diseases (IMDs) are chronic conditions that have an immunemediated etiology. Clinically, these diseases appear to be unrelated, but pathogenic pathways have been shown to connect them. While inflammation is a common occurrence in the body, it may either stimulate a favorable immune response to protect against harmful signals or cause illness by damaging cells and tissues. Nanomedicine has tremendous promise for regulating inflammation and treating IMIDs. Various nanoparticles coated with nanotherapeutics have been recently fabricated for effective targeted delivery to inflammatory tissues. RNA interference (RNAi) offers a tremendous genetic approach, particularly if traditional treatments are ineffective against IMDs. In cells, several signaling pathways can be suppressed by using RNAi, which blocks the expression of particular messenger RNAs. Using this molecular approach, the undesirable effects of anti-inflammatory medications can be reduced. Still, there are many problems with using short-interfering RNAs (siRNAs) to treat IMDs, including poor localization of the siRNAs in target tissues, unstable gene expression, and quick removal from the blood. Nanotherapeutics have been widely used in designing siRNA-based carriers because of the restricted therapy options for IMIDs. In this review, we have discussed recent trends in the fabrication of siRNA nanodelivery systems, including lipid-based siRNA nanocarriers, liposomes, and cationic lipids, stable nucleic acid-lipid particles, polymeric-based siRNA nanocarriers, polyethylenimine (PEI)-based nanosystems, chitosan-based nanoformulations, inorganic material-based siRNA nanocarriers, and hybrid-based delivery systems. We have also introduced novel siRNA-based nanocarriers to

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Progress on ocular siRNA gene‐silencing therapy and drug delivery systems

Cited by 34 publications

References 121 publications

Efficient Ocular Delivery of VCP siRNA via Reverse Magnetofection in RHO P23H Rodent Retina Explants

Efficient Ocular Delivery of VCP siRNA via Reverse Magnetofection in RHO P23H Rodent Retina Explants

USP10 Targeted Self-Deliverable siRNA to Prevent Scarring in the Cornea

siRNA‐based nanotherapeutics as emerging modalities for immune‐mediated diseases: A preliminary review

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