Small Players Ruling the Hard Game: siRNA in Bone Regeneration

Ghadakzadeh, Saber; Mekhail, Mina; Aoude, Ahmed; Hamdy, Reggie C.; Tabrizian, Maryam

doi:10.1002/jbmr.2816

Cited by 25 publications

(14 citation statements)

References 117 publications

(233 reference statements)

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“…siRNA-based therapies have been explored for a variety of diseases, such as cancer and genetic disorders [4], and only recently have gained attention for use in regenerative medicine applications [9]. However, siRNA has multiple unfavorable physicochemical characteristics hampering effective in vivo delivery [50].…”

Section: Discussionmentioning

confidence: 99%

“…Systemic delivery of siRNA, which is typically achieved using nanoparticle (NP)based delivery systems, suffers from inefficiencies due to liver accumulation and reticuloendothelial system (RES) clearance, resulting in subtherapeutic concentrations at target tissues [8]. The concomitant high doses of administered siRNA required to reach therapeutic levels result in off-target effects, limiting the safety of siRNA therapeutics [9].…”

Section: Introductionmentioning

confidence: 99%

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Controlled and sustained delivery of siRNA/NPs from hydrogels expedites bone fracture healing

2017

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Despite great potential, delivery remains as the most significant barrier to the widespread use of siRNA therapeutics. siRNA has delivery limitations due to susceptibility to RNase degradation, low cellular uptake, and poor tissue-specific localization. Here, we report the development of a hybrid nanoparticle (NP)/hydrogel system that overcomes these challenges. Hydrogels provide localized and sustained delivery via controlled release of entrapped siRNA/NP complexes while NPs protect and enable efficient cytosolic accumulation of siRNA. To demonstrate therapeutic efficacy, regenerative siRNA against WW domain-containing E3 ubiquitin protein ligase 1 (Wwp1) complexed with NP were entrapped within poly(ethylene glycol) (PEG)-based hydrogels and implanted at sites of murine mid-diaphyseal femur fractures. Results showed localization of hydrogels and controlled release of siRNA/NPs at fractures for 28 days, a timeframe over which fracture healing occurs. siRNA/NP sustained delivery from hydrogels resulted in significant Wwp1 silencing at fracture callus compared to untreated controls. Fractures treated with siRNA/NP hydrogels exhibited accelerated bone formation and significantly increased biomechanical strength. This NP/hydrogel siRNA delivery system has outstanding therapeutic promise to augment fracture healing. Owing to the structural similarities of siRNA, the development of the hydrogel platform for in vivo siRNA delivery has myriad therapeutic possibilities in orthopaedics and beyond.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Controlled and sustained delivery of siRNA/NPs from hydrogels expedites bone fracture healing

2017

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“…Much effort has been made to introduce siRNAs for the treatment of diseases for which no effective intervention exists. 4 , 5 , 6 However, many difficulties need to be overcome before such a goal can be realized. The specificity and silencing activity of siRNA are the most important issues in clinical and non-clinical applications.…”

Section: Introductionmentioning

confidence: 99%

Site-Specific Modification Using the 2′-Methoxyethyl Group Improves the Specificity and Activity of siRNAs

Song

Wang

et al. 2017

Molecular Therapy - Nucleic Acids

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Rapid progress has been made toward small interfering RNA (siRNA)-based therapy for human disorders, but rationally optimizing siRNAs for high specificity and potent silencing remains a challenge. In this study, we explored the effect of chemical modification at the cleavage site of siRNAs. We found that modifications at positions 9 and 10 markedly reduced the silencing potency of the unmodified strand of siRNAs but were well tolerated by the modified strand. Intriguingly, addition of the 2′-methoxyethyl (MOE) group at the cleavage site improved both the specificity and silencing activity of siRNAs by facilitating the oriented RNA-induced silencing complex (RISC) loading of the modified strand. Furthermore, we combined MOE modifications at positions 9 and 10 of one strand together with 2′-O-methylation (OMe) at position 14 of the other strand and found a synergistic effect that improved the specificity of siRNAs. The surprisingly beneficial effect of the combined modification was validated using siRNA-targeting endogenous gene intercellular adhesion molecule 1 (ICAM1). We found that the combined modifications eliminated its off-target effects. In conclusion, we established effective strategies to optimize siRNAs using site-specific MOE modifications. The findings may allow the creation of superior siRNAs for therapy in terms of activity and specificity.

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“…[75] Research is also being conducted in the application of siRNA in the enhancement of bone regeneration and the treatment of musculoskeletal injuries and diseases. [76] Additional research is being invested in how siRNA can be used to treat ocular pathologies by targeting the molecules that contribute to the development of glaucoma, retinitis pigmentosa, and neovascular eye diseases. Although the use of siRNA therapy for diseases in the eyes have many advantages, this type of treatment can be further enhanced with more advancements in the development of controlled/targeted delivery techniques for siRNA to the eyes.…”

Section: Sirna and Carrier Modificationsmentioning

confidence: 99%

An Overview of Various Carriers for siRNA Delivery

Marquez¹,

Madu²,

Lü³

2018

Oncomedicine

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RNA interference through the use of short interfering molecules known as short interfering RNA (siRNA) has the potential to greatly advance research in treatments for many diseases because it has the ability to silence the expression of specific genes by helping degrade target mRNA. However, challenges to siRNA delivery have made the development of safe and effective delivery systems paramount in siRNA research. Various types of delivery systems have been proposed and investigated for siRNA delivery and therapy. Although viral vectors have been established to be the most effective in delivering siRNA molecules, they also raise many concerns over biosafety, especially concerning immunogenicity. Therefore, many researchers have begun to investigate and study non-viral vectors. Non-viral vectors are studied because they are typically considered to be safer than viral vectors albeit less efficient as well. The three general non-viral vectors that have been studied for siRNA delivery are lipid-based, non-lipid organic-based, and non-lipid inorganic-based carriers. Within those general parameters of non-viral vector classification are subtypes that are each unique with their own characteristic benefits and downsides. Many of these carriers, as well as even naked siRNA, do have the potential to be modified so that siRNA delivery could be further enhanced with benefits such as greater stability and duration. Researchers still must be wary with alterations as to not interfere with siRNA function. Currently, widespread siRNA therapeutics are still out of reach, but as more advancements in siRNA research including research on their delivery mechanisms are established, the goal of integrating siRNA therapy into the treatment of a multitude of diseases becomes increasingly more of a possibility. Researchers are currently investigating how siRNA can be used to not just treat cancer but ocular and neurodegenerative diseases as well as many others. There are still many obstacles to face and overcome before siRNA therapy can be implemented into the treatment of many diseases, and more research must still be conducted concerning siRNA delivery systems. Many advancements pertaining to siRNA carriers have been made, and many more are likely on their way.

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Small Players Ruling the Hard Game: siRNA in Bone Regeneration

Cited by 25 publications

References 117 publications

Controlled and sustained delivery of siRNA/NPs from hydrogels expedites bone fracture healing

Controlled and sustained delivery of siRNA/NPs from hydrogels expedites bone fracture healing

Site-Specific Modification Using the 2′-Methoxyethyl Group Improves the Specificity and Activity of siRNAs

An Overview of Various Carriers for siRNA Delivery

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