Ocular nanoparticle toxicity and transfection of the retina and retinal pigment epithelium

Prow, Tarl W.; Bhutto, Imran Ahmed; Kim, Sahng Y.; Grebe, Rhonda; Merges, Carol; McLeod, D. Scott; Uno, Koichi; Mennon, Mohamed; Rodriguez, L. Solano; Leong, Kam W.; Lutty, Gerard A.

doi:10.1016/j.nano.2008.06.003

Cited by 98 publications

(62 citation statements)

References 13 publications

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“…Many carriers that have shown efficiency in transfecting cells and tissues still face important safety issues for practical application in medicine. [39,40] The influence of CS and DS in the cytotoxicity profile of the CG nanoparticles was evaluated in the HCE cell line. We incubated the nanoparticles with these human corneal cells at varying concentrations, ranging from 1 to 150 mg Á cm À2 , for 3 h, and their metabolic activity was measured by the XTT assay.…”

Section: Nanoparticles Cytotoxicitymentioning

confidence: 99%

Hybrid Nanoparticle Design Based on Cationized Gelatin and the Polyanions Dextran Sulfate and Chondroitin Sulfate for Ocular Gene Therapy

Zorzi

Párraga

Seijo

et al. 2011

Macromolecular Bioscience

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We describe the development of hybrid nanoparticles composed of cationized gelatin and the polyanions CS and DS for gene therapy in the ocular surface. The physicochemical properties of the nanoparticles that impact their bioperformance, such as average size and zeta potential, can be conveniently modulated by changing the ratio of polymers and the crosslinker. These systems associate plasmid DNA and are able to protect it from DNase I degradation. We corroborate that the introduction of CS or DS in the formulation decreases the in vitro toxicity of the nanoparticles to human corneal cells without compromising the transfection efficiency. These nanoparticles are potential candidates for the development of safer and more effective nanomedicines for ocular therapy.

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Section: Nanoparticles Cytotoxicitymentioning

confidence: 99%

Hybrid Nanoparticle Design Based on Cationized Gelatin and the Polyanions Dextran Sulfate and Chondroitin Sulfate for Ocular Gene Therapy

Zorzi

Párraga

Seijo

et al. 2011

Macromolecular Bioscience

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“…While in-depth toxicity studies will be conducted in future, we observe no histological or functional signs of gross retinal toxicity or degeneration following subretinal delivery of GCS NPs. This is particularly important as unmodified chitosan in the eye has been shown to induce some toxic effects [28] (although other modified chitosans, such as deoxycholic acid-substituted chitosan were shown not be cytotoxic [29] ).…”

Section: Discussionmentioning

confidence: 99%

Synthesis and Characterization of Glycol Chitosan DNA Nanoparticles for Retinal Gene Delivery

et al. 2013

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Given the number of monogenic ocular diseases and the number of non-monogenic degenerative ocular diseases for which gene therapy has been considered as a treatment, the development of effective therapeutic delivery strategies for DNA is a critical research goal. Here we generate, characterize, and evaluate non-viral nanoparticles composed of glycol chitosan (GCS) and plasmid DNA (pDNA). We show that these particles are stable, do not aggregate in saline, are resistant to DNases, and have a hydrodynamic diameter of ∼250 nm. We further show that the plasmid in these NPs maintains its proper conformation and can be released and expressed inside the cell. To determine whether these NPs would be suitable for intraocular use, pDNA carrying the ubiquitously expressed CBA-eGFP expression cassette was compacted and subretinally injected into adult WT albino mice. At post-injection (PI) day 14, we observe substantial GFP expression exclusively in the retinal pigment epithelium (RPE) in eyes treated with GCS NPs but not in uncompacted pDNA or vehicle (saline) treated eyes. We observe no signs of gross retinal toxicity and at PI-30 days, there is no difference in electroretinogram function between GCS NP-, pDNA-, or vehicle-treated eyes. These results suggest that with further development GCS NPs may be a useful addition to our available repertoire of genetic therapies for the treatment of RPE-associated diseases.

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“…PEI polyplexes have been used to transfect inner retinal cells following intravitreal injection (Liao and Yau, 2007). However, potential toxic effects have been observed with both liposomes and polyplexes when injected into the subretinal space (Charbel Issa and MacLaren, 2012; Kachi et al, 2005; Prow et al, 2008). …”

Section: Non-viral Vectorsmentioning

confidence: 99%

Vector platforms for gene therapy of inherited retinopathies

Trapani

Puppo

Auricchio

2014

Progress in Retinal and Eye Research

152

155

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Inherited retinopathies (IR) are common untreatable blinding conditions. Most of them are inherited as monogenic disorders, due to mutations in genes expressed in retinal photoreceptors (PR) and in retinal pigment epithelium (RPE). The retina’s compatibility with gene transfer has made transduction of different retinal cell layers in small and large animal models via viral and non-viral vectors possible. The ongoing identification of novel viruses as well as modifications of existing ones based either on rational design or directed evolution have generated vector variants with improved transduction properties. Dozens of promising proofs of concept have been obtained in IR animal models with both viral and non-viral vectors, and some of them have been relayed to clinical trials. To date, recombinant vectors based on the adeno-associated virus (AAV) represent the most promising tool for retinal gene therapy, given their ability to efficiently deliver therapeutic genes to both PR and RPE and their excellent safety and efficacy profiles in humans. However, AAVs’ limited cargo capacity has prevented application of the viral vector to treatments requiring transfer of genes with a coding sequence larger than 5 kb. Vectors with larger capacity, i.e. nanoparticles, adenoviral and lentiviral vectors are being exploited for gene transfer to the retina in animal models and, more recently, in humans. This review focuses on the available platforms for retinal gene therapy to fight inherited blindness, highlights their main strengths and examines the efforts to overcome some of their limitations.

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Ocular nanoparticle toxicity and transfection of the retina and retinal pigment epithelium

Cited by 98 publications

References 13 publications

Hybrid Nanoparticle Design Based on Cationized Gelatin and the Polyanions Dextran Sulfate and Chondroitin Sulfate for Ocular Gene Therapy

Hybrid Nanoparticle Design Based on Cationized Gelatin and the Polyanions Dextran Sulfate and Chondroitin Sulfate for Ocular Gene Therapy

Synthesis and Characterization of Glycol Chitosan DNA Nanoparticles for Retinal Gene Delivery

Vector platforms for gene therapy of inherited retinopathies

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