Castanotto D, Rossi JJThe promises and pitfalls of RNA-interference-based therapeutics. Nature 457:426-433

Department of Molecular Biology and City of Hope Graduate School of Biological Sciences, Beckman Research Institute of the City of Hope, Duarte, California 91010, USA.
Nature (Impact Factor: 41.46). 02/2009; 457(7228):426-33. DOI: 10.1038/nature07758
Source: PubMed


The discovery that gene expression can be controlled by the Watson-Crick base-pairing of small RNAs with messenger RNAs containing complementary sequence - a process known as RNA interference - has markedly advanced our understanding of eukaryotic gene regulation and function. The ability of short RNA sequences to modulate gene expression has provided a powerful tool with which to study gene function and is set to revolutionize the treatment of disease. Remarkably, despite being just one decade from its discovery, the phenomenon is already being used therapeutically in human clinical trials, and biotechnology companies that focus on RNA-interference-based therapeutics are already publicly traded.

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Available from: John J Rossi, Jun 22, 2015
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    • "RNA interference (RNAi) has been proven to be a useful approach to treat various genetic diseases. It can down-regulate specific protein expression by silencing the activity of its targeted gene [1] [2] [3] [4] [5]. This approach exhibits significant promises for the development of a new class of molecular therapeutic drugs that interferes with disease-causing or –promoting genes, particularly those that encode the so-called ''non-druggable'' targets not amenable to conventional therapeutics [6] [7]. "
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    ABSTRACT: RNA interference (RNAi) mediated gene silencing holds significant promises in gene therapy. A major obstacle to efficient RNAi is the systemic delivery of the therapeutic RNAs into the cytoplasmon whithout being trapped in intracellular endo-/lyso-somes. Herein we report the development of a PEGylated, RGD peptide modified, and disulfide cross-linked short polyethylenimines (DSPEIs)functionalized gold nanorod (RDG) for targeted small hairpin (sh)RNA delivery. The RDG effectively condensed shRNAs into stable nanoparticles, allowing for highly specific targeting of model human brain cancer cells (U-87 MG-GFP)viathe αvβ3integrins-mediated endocytosis. The combined effects of endosomal escape (viathe proton-sponge effect of the PEIs)and efficient cleavage of the disulfide-cross-linked DSPEIsby the high intracellular glutathione content triggered rapid cytoplasma shRNAs release resulted in excellent RNAi efficiency and low cytotoxicity. Furthermore, the high stability and prolonged blood circulation afforded by PEGylation allowed for highly effective, targeted tumor accumulation and internalization of the carriers, resulting in outstanding intra-tumor gene silencing efficiency in U-87 MG-GFP tumor bearing BALB/c mice. Combining the capabilities of both passive and active targeting, intracellular glutathione-triggered "off-on" release and endosomal escape, the RDG nanocarrier developed herein appears to be a highly promising non-viral vector for efficient RNAi. Copyright © 2015. Published by Elsevier Ltd.
    Acta biomaterialia 05/2015; 23. DOI:10.1016/j.actbio.2015.05.028 · 6.03 Impact Factor
    • "This is not surprising considering that most of the antiviral-related genes analyzed mediate the RNAi machinery , which has been demonstrated to act as an antiviral mechanism in different biological groups, including crustaceans (Labreuche and Warr, 2013; Lu et al., 2005; Robalino et al., 2005; Wilkins et al., 2005). Sid-1, argonaute and Dicer proteins, which were shown here to be up-regulated by WSSV, are directly involved in double-stranded RNA import, recognition and degradation during viral replication, respectively (Labreuche et al., 2010; Aliyari and Ding, 2009; Castanotto and Rossi, 2009; Saleh et al., 2006; Hannon, 2002; Winston et al., 2002). A similar up-regulation response of genes involved in RNAi pathway was also observed in Fenneropenaeus chinensis shrimp during an acute WSSV infection (Li et al., 2013). "
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    ABSTRACT: Disease in Pacific white shrimp Litopenaeus vannamei caused by the infectious myonecrosis virus (IMNV) causes significant socioeconomic impacts in infection-prone shrimp aquaculture regions. The use of synthetic dsRNA to activate an RNA interference (RNAi) response is being explored as a means of disease prophylaxis in farmed shrimp. Here, survival was tracked in L. vannamei injected with long synthetic dsRNAs targeted to IMNV open reading frame (ORF) 1a, ORF1b, and ORF2 genome regions prior to injection challenge with IMNV, and real-time RT-PCR was used to track the progress of IMNV infection and mRNA expression levels of the host genes sid1, dicer2, and argonaute2. Injection of dsRNAs targeting the ORF1a and ORF1b genes but not the ORF2 gene strongly inhibited IMNV replication over a 3 wk period following IMNV challenge, and resulted in 90 and 83% shrimp survival, respectively. Host gene mRNA expression data indicated that the Sid1 protein, which forms a transmembrane channel involved in cellular import/export of dsRNA, increased in abundance most significantly in shrimp groups that were most highly protected by virus-specific dsRNA injection. Subclinical IMNV infections present in the experimental L. vannamei used increased markedly in the 2 d between injection of any of the 4 virus-specific or non-specific dsRNAs tested and IMNV challenge. While handling and injection stress are implicated in increasing IMNV replication levels, the underlying molecular factors that may have been involved remain to be elucidated.
    Diseases of Aquatic Organisms 05/2015; 114(2). DOI:10.3354/dao02853 · 1.75 Impact Factor
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    • "The importance and applications of transition metal–ligand complexes are widespread from synthetic chemistry to material science and biochemistry. These metals have been used for drug design and delivery [12] [13] [14] [15] [16] [17], catalysis [18] [19] [20] [21], solar cell applications [22] [23] [24], and biological imaging [25] [26]. In biological systems , transition metals are involved with very specific structural and cellular functions. "
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    ABSTRACT: Some transition metal complexes of phenylalanine of general formula [M(C9H10NO2)2]; where M=Mn(II), Co(II), Ni(II), Cu(II) and Zn(II) are prepared in aqueous medium and characterized by spectroscopic, thermo-gravimetric (TG) and magnetic susceptibility analysis. Density functional theory (DFT) has been employed calculating the equilibrium geometries and vibrational frequencies of those complexes at B3LYP level of theory using 6-31G(d) and SDD basis sets. In addition, frontier molecular orbital and time-dependent density functional theory (TD-DFT) calculations are performed with CAM-B3LYP/6-31+G(d,p) and B3LYP/SDD level of theories. Thermo-gravimetric analysis confirms the composition of the complexes by comparing the experimental and calculated data for C, H, N and metals. Experimental and computed IR results predict a significant change in vibrational frequencies of metal-phenylalanine complexes compared to free ligand. DFT calculation confirms that Mn, Co, Ni and Cu complexes form square planar structure whereas Zn adopts distorted tetrahedral geometry. The metal-oxygen bonds in the optimized geometry of all complexes are shorter compared to the metal-nitrogen bonds which is consistent with a previous study. Cation-binding energy, enthalpy and Gibbs free energy indicates that these complexes are thermodynamically stable. UV-vis and TD-DFT studies reveal that these complexes demonstrate representative metal-to-ligand charge transfer (MLCT) and d-d transitions bands. TG analysis and IR spectra of the metal complexes strongly support the absence of water in crystallization. Magnetic susceptibility data of the complexes exhibits that all except Zn(II) complex are high spin paramagnetic. Copyright © 2014 Elsevier B.V. All rights reserved.
    Spectrochimica Acta Part A Molecular and Biomolecular Spectroscopy 11/2014; 138:499-508. DOI:10.1016/j.saa.2014.11.084 · 2.35 Impact Factor
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