Design and Creation of New Nanomaterials for Therapeutic RNAi

Baigude, Huricha; McCarroll, Joshua A.; Yang, Chyun-Yu; Swain, Pamela; Rana, Tariq M.

doi:10.1021/cb7000582

Cited by 73 publications

(75 citation statements)

References 26 publications

(43 reference statements)

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“…An interesting nanoparticle delivery system has been reported that can mask the immunostimulatory effects of siRNAs, even those containing known immunostimulatory sequences 97 100 reported the use of nanoparticles composed of a lysine-based amino acid backbone with lipid functional groups (iNOPs) to deliver APOBtargeting siRNAs in vitro and in vivo. The same system was later adapted to deliver anti-miRs, which significantly decreased miR-122 expression in the liver of mice 101 .…”

Section: In Vivo Delivery Strategiesmentioning

confidence: 99%

Therapeutic targeting of microRNAs: current status and future challenges

Rana

2014

Nat Rev Drug Discov

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888

744

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MicroRNAs (miRNAs) are evolutionarily conserved small non-coding RNAs that have crucial roles in regulating gene expression. Increasing evidence supports a role for miRNAs in many human diseases, including cancer and autoimmune disorders. The function of miRNAs can be efficiently and specifically inhibited by chemically modified antisense oligonucleotides, supporting their potential as targets for the development of novel therapies for several diseases. In this Review we summarize our current knowledge of the design and performance of chemically modified miRNA-targeting antisense oligonucleotides, discuss various in vivo delivery strategies and analyse ongoing challenges to ensure the specificity and efficacy of therapeutic oligonucleotides in vivo. Finally, we review current progress on the clinical development of miRNA-targeting therapeutics.

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Section: In Vivo Delivery Strategiesmentioning

confidence: 99%

Therapeutic targeting of microRNAs: current status and future challenges

Rana

2014

Nat Rev Drug Discov

Self Cite

888

744

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“…7 Among these approaches, the most efficient systemic administration was achieved using stable nucleic acid lipid particles. 4 However, a therapeutic dose (2.5 mg/kg) of these particles, when administered in cynomolgus monkeys, caused marked liver damage.…”

Section: Introductionmentioning

confidence: 99%

Efficient In Vivo Delivery of siRNA to the Liver by Conjugation of α-Tocopherol

et al. 2008

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RNA interference is a powerful tool for target-specific knockdown of gene expression. However, efficient and safe in vivo delivery of short interfering RNA (siRNA) to the target organ, which is essential for therapeutic applications, has not been established. In this study we used alpha-tocopherol (vitamin E), which has its own physiological transport pathway to most of the organs, as a carrier molecule of siRNA in vivo. The alpha-tocopherol was covalently bound to the antisense strand of 27/29-mer siRNA at the 5'-end (Toc-siRNA). The 27/29-mer Toc-siRNA was designed to be cleaved by Dicer, producing a mature form of 21/21-mer siRNA after releasing alpha-tocopherol. The C6 hydroxyl group of alpha-tocopherol, associated with antioxidant activity, was abolished. Using this new vector, intravenous injection of 2 mg/kg of Toc-siRNA, targeting apolipoprotein B (apoB), achieved efficient reduction of endogenous apoB messenger RNA (mRNA) in the liver. The downregulation of apoB mRNA was confirmed by the accumulation of lipid droplets in the liver as a phenotype. Neither induction of interferons (IFNs) nor other overt side effects were revealed by biochemical and pathological analyses. These findings indicate that Toc-siRNA is effective and safe for RNA interference-mediated gene silencing in vivo.

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“…injection of clinically relevant doses of siRNA (21). More recently, another lipid-based system termed interfering nanoparticles (iNOPs) has also demonstrated the ability to deliver siRNA in vivo (23). A key drawback of the SNALP and iNOP systems, however, is that the siRNA complexes are only passively targeted to liver.…”

mentioning

confidence: 99%

Dynamic PolyConjugates for targeted in vivo delivery of siRNA to hepatocytes

Rozema

Lewis

Wakefield

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

609

624

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Achieving efficient in vivo delivery of siRNA to the appropriate target cell would be a major advance in the use of RNAi in gene function studies and as a therapeutic modality. Hepatocytes, the key parenchymal cells of the liver, are a particularly attractive target cell type for siRNA delivery given their central role in several infectious and metabolic disorders. We have developed a vehicle for the delivery of siRNA to hepatocytes both in vitro and in vivo, which we have named siRNA Dynamic PolyConjugates. Key features of the Dynamic PolyConjugate technology include a membrane-active polymer, the ability to reversibly mask the activity of this polymer until it reaches the acidic environment of endosomes, and the ability to target this modified polymer and its siRNA cargo specifically to hepatocytes in vivo after simple, low-pressure i.v. injection. Using this delivery technology, we demonstrate effective knockdown of two endogenous genes in mouse liver: apolipoprotein B (apoB) and peroxisome proliferator-activated receptor alpha (ppara). Knockdown of apoB resulted in clear phenotypic changes that included a significant reduction in serum cholesterol and increased fat accumulation in the liver, consistent with the known functions of apoB. Knockdown of ppara also resulted in a phenotype consistent with its known function, although with less penetrance than observed in apoB knockdown mice. Analyses of serum liver enzyme and cytokine levels in treated mice indicated that the siRNA Dynamic PolyConjugate was nontoxic and well tolerated.pH labile bonds ͉ nonviral siRNA delivery ͉ siRNA-polymer conjugates ͉ endosomolytic polymers

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Design and Creation of New Nanomaterials for Therapeutic RNAi

Cited by 73 publications

References 26 publications

Therapeutic targeting of microRNAs: current status and future challenges

Therapeutic targeting of microRNAs: current status and future challenges

Efficient In Vivo Delivery of siRNA to the Liver by Conjugation of α-Tocopherol

Dynamic PolyConjugates for targeted in vivo delivery of siRNA to hepatocytes

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