MicroRNA Interference Technologies
Even siRNAs with their limited target promiscuity due to their exquisite sequence complementarity requirement have the potential to have side effects given how far upstream these effector molecules are of multiple signaling pathways. In some instances, off-target effects may actually provide additional benefit as can be inferred from miRp for skin care.
This miRNA post-transcriptionally targets TYR, which has utility in treating aberrant skin pigmentation but also down-modulates expression of HYAL, which can add a moisturizing benefit. Regardless, efforts have already been described to limit the side targets of miRp and allow for safe miRNA-induced reduction in TYR activity [ 67 , ].
Combining the knowledge gleaned from miRNA-profiling efforts and the artificial refinement and narrowing of the associated targets for a particular miRNA will greatly improve the safety of RNAi-based treatments. Current experimental topical delivery platforms for RNAi-based therapeutics described herein have attempted to surmount the skin barrier either through novel lipid chemistries allowing for ultra-flexible liposomes or through the incorporation of skin-penetrating peptides into the liposome bilayer. Topical application of prospective RNAi-based treatments is an attractive mode of delivery for a variety of reasons articulated in this review, and the breakthrough vehicle will likely employ a combination of the strategies outlined.
Liposomes represent a well-developed technology, and large-scale production is possible with relative ease. Therefore, the production of peptide-modified ultra-flexible liposomes for the enhanced penetration of RNAi effector molecules into the skin should prove to be an economically attractive platform for both cosmetic and pharmaceutical industries. A final consideration for the development and commercialization of RNAi-based treatments for skin conditions, and indeed for other types of disease, is that these effector molecules allow for the targeting of disease pathways that were previously undruggable by standard treatment approaches [ ].
Particularly when contemplating therapeutic strategies for genetic diseases, especially those manifesting from a single nucleotide polymorphism, standard methodologies with conventional drugs fall short [ ]. The validation and scale-up design of a cost-effective delivery system for siRNAs and miRNAs will be the critical factor in unleashing the power of the RNAi-based therapeutics: a new class of treatments that empower cells to repair themselves. The authors of this manuscript wish to thank Mr. Isaiah Negron and Ms. Brianna Tokar for their objective review of this manuscript, fruitful discussions, and suggested revisions.
No funding was received by either author toward the preparation of this manuscript. Paul Lawrence, Phone: , Email: moc. Joseph Ceccoli, Phone: , Email: moc. National Center for Biotechnology Information , U. Published online Sep 5. Paul Lawrence and Joseph Ceccoli. Author information Copyright and License information Disclaimer. Corresponding author. This article has been cited by other articles in PMC.
Abstract The advent of RNA interference RNAi technology has profoundly impacted molecular biology research and medicine but has also advanced the field of skin care. Key Points The relative contributions of various microRNAs to the pathogenesis of an increasing number of skin conditions have been elucidated as a result of expanded microRNA profiling efforts.
Mimics and antagomiRs of microRNAs that have been implicated in the pathogenesis of certain skin diseases have been tested in vitro and in vivo as therapeutic agents. Both ultra-flexible liposomes and skin-penetrating peptides complexed with microRNA-based therapeutics have demonstrated utility as topical delivery platforms capable of transporting microRNAs across the skin barrier. Open in a separate window. Introduction Skin Disorders and Diseases The skin represents the primary barrier protecting the body from a horde of environmental insults.
Differential miRNA Profiles A variety of biological samples have been examined for differential regulation of miRNA populations in response to certain disease conditions, including cancer, bacterial infections, and viral infections [ 43 , 44 ]. Therapeutic Application of miRNAs As more miRNAs have been identified as key players in the molecular pathogenesis of cancer and infectious diseases, so too has the number of miRNAs implicated in the manifestation of various skin disorders and diseases.
Skin Pigmentation Multiple skin pigmentation disorders would potentially benefit from miRNA-based therapeutic applications, including vitiligo, albinism, aging spots such as solar lentigo , freckles, and melasma. Skin Aging Skin aging occurs via either intrinsic or extrinsic means [ 39 ]. Acne Skin acne afflicts more than million people globally and frequently ranks as the eighth most common disease among humans. Psoriasis Psoriasis represents a severe auto-immune disease of the skin that is often characterized by abnormal patches of red, itchy, scaly skin.
Atopic Dermatitis Atopic dermatitis or atopic eczema is a skin disorder similar to but distinct from psoriasis and other forms of dermatitis and is characterized by itchy, red, swollen, and cracked skin. Topical miRNA Delivery Platforms A variety of methodologies are currently being developed for the deployment of miRNA-based therapeutics for multiple skin diseases and disorders. Liposomes Conventional liposomes are frequently employed for the deployment of miRNAs and other RNAi molecules in both in vitro and in vivo settings, but these lipid-based carrier vehicles are usually introduced by injection, not by topical application.
Cell-Penetrating Peptides Cell-penetrating peptides CPPs have also been explored in some instances for their ability to bind nucleic acids covalently or non-covalently and facilitate their entry through the skin [ ]. Chitosan Chitosan protein has been investigated for its usage in a variety of bio-medical applications, particularly in the area of wound healing [ , ]. Concluding Remarks The recent advances in the identification of miRNAs that contribute to various skin conditions open up a whole new arena of skin care therapeutics.
Acknowledgements The authors of this manuscript wish to thank Mr. Compliance with ethical standards Conflict of interest The authors of this manuscript have no conflicts of interest. Funding No funding was received by either author toward the preparation of this manuscript. References 1. Structure and function of the epidermis related to barrier properties. Clin Dermatol. Bikle DD, Pillai S. Vitamin D metabolite production and function in keratinocytes.
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J Cell Mol Med. MicroRNAa suppresses ILmediated skin inflammation and is genetically associated with psoriasis. J Allergy Clin Immunol. J Immunol. MiR is down-regulated in psoriasis and promotes keratinocyte differentiation via targeting GRHL2. Identifying targets for topical RNAi therapeutics in psoriasis: assessment of a new in vitro psoriasis model. Arch Dermatol Res. An exploration of the role of MicroRNAs in psoriasis: a systematic review of the literature. Medicine Baltimore ; 94 :e IGFBP7 as a potential therapeutic target in psoriasis. Rebane A. Adv Exp Med Biol. MicroRNAa alleviates chronic skin inflammation in atopic dermatitis through suppression of innate immune responses in keratinocytes.
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Adv Drug Deliv Rev. A new potent secondary amphipathic cell-penetrating peptide for siRNA delivery into mammalian cells. Protein transduction: cell penetrating peptides and their therapeutic applications. Curr Med Chem. Cholesteryl oligoarginine delivering vascular endothelial growth factor siRNA effectively inhibits tumor growth in colon adenocarcinoma. Hsu T, Mitragotri S. Delivery of siRNA and other macromolecules into skin and cells using a peptide enhancer. Of the reagents used to inhibit the overexpressed miRNAs the antimirs are most frequently used. These single-stranded antisense reagents that inhibit the RISC-bound miRNAs 45 differ in their length ranging from 16 nt to 31 nt , To increase their nuclease resistance and the stability of their interactions with target miRNAs the antimirs were subjected to various chemical modifications.
The stability of the miRNA-antimir interaction was strongly enhanced after extending the antimir sequence with the flanks forming a double-stranded structure Such antimirs were shown to be functional at sub-nanomolar concentrations. For in vivo applications, the cholesterol-conjugated and thio-modified antimirs were successfully used 47 , Taken together, still very little is known about the toxicity of various reagents used by miRNA technology.
Yet, the relevant knowledge may be gained from more numerous applications of the RNAi and antisense technologies that use reagents of similar types and lengths and which are stabilized with the same or similar chemistries. One general conclusion that could be drawn from these studies is that RNAs recognized by cells as self that resemble cellular transcripts in terms of structure and localization are rather tolerated, while those recognized as foreign induce various responses depending on their structural features, the way they entered the cell and the cellular compartment they localize , , Like viral invasion, cell transfection with RNAi or miRNA reagent often results in the increased expression levels of primary sensors of non-self RNA and other proteins of the innate immune system.
The increased levels of proteins have typically their source in upregulated transcripts. By now, the most frequently used tests rely on the measurement of systemic cytokine and type-1 IFN release into the blood of treated animals, supported by cytokine release assays from primary immune cell cultures in vitro 67 , A survey of relevant literature shows, however, that the question of the activation of the immune system by various RNAi triggers and miRNA regulators is rarely addressed in a comprehensive way, some studies address it only fragmentarily and most studies do not address it at all Supplementary Data.
This situation will likely change with the increased number of in vivo applications of the RNAi and miRNA technologies in which the safety issues need to be thoroughly considered. The common theme is also the misuse of tests for immune response activation. While testing non-specific cellular responses to foreign RNA one should also carefully analyze the effect caused by the delivery system itself. It has been shown with the use of microarrays that both Lipofectin and Oligofectamine altered the expression of many genes in human A epithelial cells The affected genes are functionally involved in various cellular processes, including cell proliferation, differentiation and apoptosis.
The identified sources of sequence-non-specific toxic effects presented and commented in this and previous sections gave rise to a set of guidelines that may help to use the RNAi technology more safely. HEK, HeLa are less,. To gain a more complete insight into the changes in gene expression that occur upon the delivery of RNAi triggers, miRNA mimetics and miRNA inhibitors functional genomics and proteomics approaches were used in several studies.
These efforts were primarily aimed at revealing the scale of sequence-specific target-off effects in various RNAi applications 72 , 73 and identifying messenger RNAs and proteins regulated by specific miRNAs rather than on finding new sequence-non-specific sensors and responders to foreign RNA. In spite of that, in several studies the latter aspect was also investigated.
The first proteomic analysis of HeLa cells transfected with the miR-1 mimetic revealed a down-regulation of 12 out of investigated proteins More recently, the same method and its modified version were used along with microarray analysis to study the effects of other miRNA mimetics on the levels of nuclear and whole-cell proteins in HeLa cells. The analyses have shown that the group of repressed proteins corresponds well to that of transcripts undergoing degradation. This would mean that transcript analysis alone may be sufficient to reveal the identity of most of the proteins regulated by miRNAs The relationships between the cellular levels of specific miRNAs, mRNAs and proteins found in these studies were shown to be functional as the same groups of transcripts and proteins responded to miRNA inhibition by specific antisense LNA oligonucleotide Neither study considered the problem of cell defense system activation by miRNA mimetics and inhibitors that were delivered to cells on different carriers and at different concentrations.
This aspect therefore needs to be addressed in further analyses of proteomes perhaps derived from more immunoresponsive cells than HeLa treated with the tools of RNAi and miRNA technologies. The search for further cellular sensors and responders to foreign RNA using functional genomics and proteomics approaches and basing on the simple criterion of transcript or protein upregulation may not be, however, a simple task.
A recent report shows that the transfections of numerous different miRNAs and siRNAs to cells may result besides the downregulation of intended and unintended transcripts also in the upregulation of a myriad of transcripts that are otherwise suppressed by endogenous miRNAs in untreated cells The available information on the sequence non-specific, toxic effects of various RNAi reagents strongly outnumbers the regarding reagents of miRNA technology Supplementary Data.
Advances in the Application and Impact of MicroRNAs as Therapies for Skin Disease
This disparity is caused at large by a time delay with which the development of miRNA technology has begun and by the lower number of its published applications. In spite of being far from satisfactory, information on the toxic effects of RNAi triggers that has been gathered thus far has provided some useful guidelines on how to use RNAi more specifically and more safely. Much of the successful research has been focused at unrevealing the sequence and structure features of RNAi reagents that cause immunostimulation.
Also, chemistry made a substantial contribution in developing less toxic and more stable reagents by placing specific chemical modifications at well selected siRNA positions. Less attention has been paid to the toxic effects of various carriers used to deliver the RNA reagents to cells. However, the already existing data shows that the carriers should no longer be considered neutral delivery vehicles. The number of available RNA carriers is large and their effects on gene expression need to be more widely and more carefully analyzed. There are also other issues relevant to sequence-non-specific responses that need to be addressed in further research.
These issues include the need for: clarifying still controversial facts regarding the immunostimulatory siRNA features, reducing strong toxic effects caused by genetic vectors used to express siRNA and miRNA in cells, and a wider application of functional genomics and proteomics approaches to find new foreign RNA sensors and responders as well as safer RNA carriers. It would be also advisable to establish a database of the toxic effects caused by RNAi and miRNA reagents for which the data presented in Supplementary Data might serve as an inspiration.
We anticipate that both the RNAi and miRNA technology will benefit, in the short term, from more widespread applications of well-designed simple toxicity tests. Such tests should be dedicated to provide answers which of the presently known RNA sensors and immune responders are activated by specific reagents in specific cells and tissues. In the long run, the next generation of such tests should be developed and based on more complete information on toxic RNA sensors and responders gained from transcriptomics and proteomics approaches.
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