Erratum

Tolentino, Michael J.; Brucker, Alexander J.; Fosnot, Joshua; Ying, Gui‐Shuang; Wu, I-Hui; Malik, Gulraiz; Wan, Shanhong; Reich, S.J.

doi:10.1097/00006982-200408000-00039

Cited by 33 publications

(9 citation statements)

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“…A typical result is that 40% of laser lesions in control eyes result in vessel growth and Grade IV leakage, whereas this percentage is reduced to 15–30% in eyes receiving anti-angiogenic treatments (Zahn et al, 2009b). Group sizes of 8–10 monkeys are typically required to document significant effects, and in some studies smaller group sizes have generated inconclusive results (Tolentino et al, 2004a,b; Zahn et al, 2009b). …”

Section: Non-human Primate Models Of Wet Macular Degenerationmentioning

confidence: 99%

Animal models of age related macular degeneration

Pennesi

Neuringer

Courtney

2012

Molecular Aspects of Medicine

316

292

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Age related macular degeneration (AMD) is the leading cause of vision loss of those over the age of 65 in the industrialized world. The prevalence and need to develop effective treatments for AMD has lead to the development of multiple animal models. AMD is a complex and heterogeneous disease that involves the interaction of both genetic and environmental factors with the unique anatomy of the human macula. Models in mice, rats, rabbits, pigs and non-human primates have recreated many of the histological features of AMD and provided much insight into the underlying pathological mechanisms of this disease. In spite of the large number of models developed, no one model yet recapitulates all of the features of human AMD. However, these models have helped reveal the roles of chronic oxidative damage, inflammation and immune dysregulation, and lipid metabolism in the development of AMD. Models for induced choroidal neovascularization have served as the backbone for testing new therapies. This article will review the diversity of animal models that exist for AMD as well as their strengths and limitations.

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Section: Non-human Primate Models Of Wet Macular Degenerationmentioning

confidence: 99%

Animal models of age related macular degeneration

Pennesi

Neuringer

Courtney

2012

Molecular Aspects of Medicine

316

292

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“…In vivo gene silencing with siRNA has been reported using both viral vector delivery and high-pressure, high-volume intravenous injection of synthetic siRNAs, but these approaches have limited, if any, clinical use (7–10). SiRNA delivery has been effective by injections directly into the tumor, or into the thecal, vitreal, nasal, or joint cavities (11–14). The only study to show in vivo uptake and associated target downregulation after normal systemic dosing required chemical modulation of the siRNA that may have unknown toxicities, and may affect siRNA activity and longevity (15).…”

Section: Introductionmentioning

confidence: 99%

Preclinical Mammalian Safety Studies of EPHARNA (DOPC Nanoliposomal EphA2-Targeted siRNA)

Wagner

Mitra

McArthur

et al. 2017

Molecular Cancer Therapeutics

103

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To address the need for efficient and biocompatible delivery systems for systemic siRNA delivery, we developed 1,2-Dioleoyl-sn-Glycero-3-Phosphatidylcholine (DOPC) nanoliposomal EphA2-targeted therapeutic (EPHARNA). Here, we performed safety studies of EPHARNA in murine and primate models. Single dosing of EPHARNA was tested at 5 concentrations in mice (N=15 per group) and groups were sacrificed on days 1, 14, and 28 for evaluation of clinical pathology and organ toxicity. Multiple dosing of EPHARNA was tested in mice and Rhesus macaques twice weekly at two dose levels in each model. Possible effects on hematologic parameters, serum chemistry, coagulation, and organ toxicity were assessed. Following single dose EPHARNA administration to mice, no gross pathological or dose-related microscopic findings were observed in either the acute (24 hrs) or recovery (14 and 28 days) phases. The no-observed-adverse-effect level (NOAEL) for EPHARNA is considered > 225 μg/kg when administered as a single injection intravenously in CD-1 mice. With twice weekly injection, EPHARNA appeared to stimulate a mild to moderate inflammatory response in a dose-related fashion. There appeared to be a mild hemolytic reaction in the female mice. In Rhesus macaques, minimal to moderate infiltration of mononuclear cells was found in some organs including the GI tract, heart, and kidney. No differences attributed to EPHARNA were observed. These results demonstrate that EPHARNA is well tolerated at all doses tested. These data, combined with previously published in vivo validation studies, have led to an ongoing first-in-human Phase I clinical trial (NCT01591356).

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“…In vivo activity was demonstrated by Lewis et al [73] and McCaffrey et al [74] when siRNA was delivered intravenously and intraperitoneally, respectively. Since then siRNA has been given systemically via large volume hydrodynamic tail vein injections (see Table 2), and locally to a number of anatomically and functionally diverse organs including the lungs, the eye, and the central nervous system [75][76][77][78][79][80][81][82][83][84][85][86].…”

Section: Delivery Strategies For Sirna In Vivomentioning

confidence: 99%

“…The delivery of siRNA to the eye has been successful in the form of intravitreal injections in non-human primates (cyanomongus monkeys) [81], and by subretinal injections to mice [78]. In both studies siRNA targeting VEGF was used to prevent laser induced choroidal neovascularisation.…”

Section: Intraocular Deliverymentioning

confidence: 99%

“…In both studies siRNA targeting VEGF was used to prevent laser induced choroidal neovascularisation. In primates the effect of a single injection of siRNA persisted for at least 36 days [81]. In mice subretinal injection of siRNA 36 hours after laser treatment resulted in a 75% reduction in neovascularization when compared with control [78].…”

Section: Intraocular Deliverymentioning

confidence: 99%

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Delivery Strategies for siRNA-mediated Gene Silencing

Gilmore¹,

Fox²,

Hollins³

et al. 2006

CDD

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RNA interference (RNAi) represents a promising new gene silencing technology for functional genomics and a potential therapeutic strategy for a variety of genetic diseases. RNAi involves the targeted post-transcriptional degradation of messenger RNA thereby inhibiting the synthesis of the desired protein. This effectively leads to silencing of gene expression. The effectors of this process are short interfering RNA (siRNA) duplexes (approximately 21-23nt) that are key intermediaries in the specific degradation of target mRNA following incorporation into the RNA-induced silencing complex (RISC) in the cytosol. However, due to the large molecular weight and negative charge of siRNA duplexes the effective cellular uptake and intracellular delivery appear to represent a major challenge for the widespread use of RNAi in vivo. This review summarises some of the main delivery strategies that have been attempted for the transfection of siRNA to cells in vitro and in vivo.

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Erratum

Cited by 33 publications

References 0 publications

Animal models of age related macular degeneration

Animal models of age related macular degeneration

Preclinical Mammalian Safety Studies of EPHARNA (DOPC Nanoliposomal EphA2-Targeted siRNA)

Delivery Strategies for siRNA-mediated Gene Silencing

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