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WIREs Nanomed Nanobiotechnol
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Nanoparticle‐motivated gene delivery for ophthalmic application

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Ophthalmic gene therapy is an intellectual and intentional manipulation of desired gene expression into the specific cells of an eye for the treatment of ophthalmic (ocular) genetic dystrophies and pathological conditions. Exogenous nucleic acids such as DNA, small interfering RNA, micro RNA, and so on, are used for the purpose of managing expression of the desired therapeutic proteins in ocular tissues. The delivery of unprotected nucleic acids into the cells is limited because of exogenous and endogenous degradation modalities. Nanotechnology, a promising and sophisticated cutting edge tool, works as a protective shelter for these therapeutic nucleic acids. They can be safely delivered to the required cells in order to modulate anticipated protein expression. To this end, nanotechnology is seen as a potential and promising strategy in the field of ocular gene delivery. This review focused on current nanotechnology modalities and other promising nonviral strategies being used to deliver therapeutic genes in order to treat various devastating ocular diseases. WIREs Nanomed Nanobiotechnol 2015, 8:160–174. doi: 10.1002/wnan.1356 This article is categorized under: Nanotechnology Approaches to Biology > Nanoscale Systems in Biology
Diagrams of vertebrate eye (left) and the retina (right).
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Simple representation of (a) lipoplex, where lipid molecules can form bilayer structures and are thus able to encapsulate hydrophilic nucleic acids inside the nanoparticle core. The lipid coating can be used with different targeting agents. The polyethylene glycol (PEG) can also work as a shielding element to protect the nucleic acids from harsh extracellular and intracellular nuclease, as well as lysosomal environments, and (b) polyplex, where morphology of the nano‐composites depend primarily on the chemical structure and charge of the constituent polymer compound (s). The negatively charged nucleic acids and positively charged polymers (via electrostatic interactions) constitute the compacted charge‐neutral DNA nanoparticles. The PEG block shields the nanocompactions and protects it from nuclease and other degradative pathways.
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Chemical structures of commonly used nonviral compounds for ocular gene delivery. (a) Chemical structures of lipid‐based compounds and (b) chemical structures of some frequently used polymeric compounds.
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Representative 25 nm icosahedral capsid of adeno‐associated virus (AAV) virion. The ∼5 kb AAV genome is packaged within the nonenveloped capsid. A gene of interest is inserted between the inverted terminal repeats under the control of promoter at upstream.
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(a) Photo activation leads to an isomerization of 11‐cis retinal molecule to all‐trans retinal (atRAL) in rhodopsin (conjugation of rod opsin + 11‐cis retinal) pigment in outer segment disc. The atRAL is now converted to all‐trans retinol (atROL) by all‐trans retinol dehydrogenase (atRDH8) and initiates visual phototransduction processes. (b) Simple representation of the visual cycle in vertebrate eye. In rod cell, retinal chromophore (11‐cis retinal) binds to the rhodopsin protein and forms G protein‐coupled receptor. Absorption of light causes activation of this photopigment and leads to isomerization of the 11‐cis retinal to atRAL that is subsequently reduced by atRDH8 to atROL in photoreceptor outer segment. This atROL is now transferred to retinal‐pigmented epithelium (RPE) cells via interphotoreceptor retinoid‐binding proteins (IRBP) carrier enzymes, where it is esterified to long‐chain fatty acids (all‐trans retinyl esters) by lecithin retinol acyltransferase. All‐trans retinyl esters are then enzymatically isomerized and hydrolyzed to the 11‐cis retinol by retinal pigment epithelium‐specific 65 kDa isomerohydrolase. This 11‐cis retinol is then finally converted to 11‐cis retinal, a universal chromophore for visual pigment, by 11‐cis retinol dehydrogenase (RDH5), and is consequently shuttled back to photoreceptor cells by IRBP to reconstitute rhodopsin pigment in photoreceptor disc, where it completes the visual cycle.
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